Orthopedic implant having a crystalline gallium-containing hydroxyapatite coating and methods for making the same

ABSTRACT

An orthopedic implant having a metal surface and a hydroxyapatite layer comprising gallium ions therein disposed on at least part of the metal surface is described. The hydroxyapatite layer has an average crystallite size of less than about 75 nm in at least one direction and dissolves for more than 2 hours in vitro. The hydroxyapatite layer is substantially free of carbonate. The coating, which is formed on a sodium titanate surface, has increased shear strength and tensile strength. The coating is formed by a solution deposited hydroxyapatite process under inert conditions. The pH of the solution varies by less than 0.1 pH unit/hour during coating formation.

CROSS-REFERENCE TO RELATED APPLICATIONS

Cross reference is made to copending U.S. patent application Ser. No.______ entitled “ORTHOPEDIC IMPLANT HAVING A CRYSTALLINE CALCIUMPHOSPHATE COATING AND METHODS FOR MAKING THE SAME” (Attorney Docket No.265280-259106, DSP5297USNP), which is hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates generally to a gallium-containinghydroxyapatite coating, and more particularly to an orthopedic implanthaving a solution deposited gallium-substituted hydroxyapatite coatingand methods for making the same.

BACKGROUND OF THE INVENTION

Bone repair often involves the use of orthopedic implants to replacemissing bone or support bone during the healing process. It is typicallydesirable to coat such orthopedic implants with osteoconductivematerials to encourage bone growth or biological fixation.

Hydroxyapatite (HA) is a naturally occurring mineral found in bones andteeth. Studies have shown that HA is osteoconductive, and orthopedicimplants have been coated with HA for this reason. Various processes forcoating implants with HA are known. One process used for coatingimplants is plasma spray. In this process, HA powder is fed into a hightemperature torch with a carrier gas. The HA powder is partially meltedand then impacts the substrate at high velocity whereupon it is rapidlyquenched back to room temperature. This process produces a mixture ofHA, other calcium phosphate phases, and amorphous calcium phosphate.These phases have wide differences in solubility in vivo. As a result,plasma sprayed hydroxyapatite (PSHA) films do not uniformly dissolve ordegrade in vivo. This non-homogenous degradation can generateparticulates in the vicinity of the implant which can result in aninflammatory cascade leading to osteolysis. The particles may also findtheir way into joint articular surfaces, resulting in increased wear.Finally, the process is not well suited for coating porous structures ofcementless implants because it is a “line of sight” process. PSHAprocessing or post processing methods can be applied that result inhighly crystalline coatings with long resorption times in-vivo. Thisattribute gives rise to concerns over long term delamination of theserelatively thick stable coatings.

Other methods to produce HA coatings for biological fixation includephysical methods such as sputtering, evaporation, and chemical vapordeposition. These physical methods do not reproduce thenano-crystallinity and high surface area of biological apatites, and theresulting coatings may not uniformly dissolve and may releaseparticulates.

Solution (or suspension) methods for producing HA coatings have alsobeen attempted. For example, Zitelli, Joseph P. and Higham, Paul (2000),A Novel Method For Solution Deposition of Hydroxyapatite Onto ThreeDimensionally Porous Metallic Surfaces: Peri-Apatite HA describes aprocess that involves producing a slurry of finely divided HA particlesinto which implants are placed and coated by accretion of the slurryparticles. High surface area, microcrystalline coatings are produced,but their adhesion to the substrate is poor.

Electrochemically assisted solution deposition has also been developed.In this process, a voltage exceeding that necessary to hydrolyze wateris applied to an implant while the implant is suspended in an aqueoussolution. This process results in deposition of calcium phosphatematerial on the implant. Typically, the deposited film is a mixture ofcalcium phosphate (CaP) phases and requires post processing to convertthe films to phase pure HA. Poor adhesion is also a concern with thesefilms. Finally, control of electrochemical currents on porous implantswith irregular particles is challenging, making this process difficultto scale.

Biomimetic processes have also been developed. These processes employsolutions mimicking body fluid concentrations and are typicallyperformed near body temperature. These processes can yield bone-likeapatite but require days or weeks to produce films a few microns thick.Attempts to increase rates associated with such methods have led tocomplications in reproducibly controlling pH, deposition rate, andaccretion rate compared to crystalline growth on the surface of theimplant. Films formed at higher rates have been found to containamorphous material. Uncontrolled deposition rate also makes it difficultto achieve target coating weights or thicknesses.

There have been previous attempts to add gallium (Ga) to apatitecoatings. However, prior methods have been unsuccessful at doping Gaions into the hydroxyapatite lattice such that specific calcium sitesundergo substitution.

As described above, hydroxyapatite coatings may be applied to orthopedicimplants to enhance osteoconductivity using methods that are eitherrapid but lead to coatings having certain undesirable or unpredictableproperties or lead to more desirable products but can take days to form.What is needed is a conformal calcium phosphate coating that can berapidly formed and has a microstructure that lends itself to uniformdegradation over a period of several weeks without generatingparticulates.

SUMMARY OF THE DISCLOSURE

Several embodiments of the invention are described by the followingenumerated clauses:

1. An orthopedic implant comprising a metal surface and a hydroxyapatitelayer disposed on at least part of the metal surface, the hydroxyapatitelayer comprising gallium ions therein, wherein the hydroxyapatite layeris crystalline.

2. An orthopedic implant comprising a metal surface and a hydroxyapatitelayer disposed on at least part of the metal surface, the hydroxyapatitelayer comprising gallium ions therein, wherein the hydroxyapatite layerhas an average crystallite size of less than about 75 nm in the [001]direction.

3. An orthopedic implant comprising a metal surface and a hydroxyapatitelayer disposed on at least part of the metal surface, the hydroxyapatitelayer comprising gallium ions therein, wherein the hydroxyapatite layer,when subjected to XRD, produces a (002) XRD peak and a (112) XRD peak,and the (002) XRD peak has an intensity 1.5 to 10 times greater than the(112) XRD peak.

4. An orthopedic implant comprising a metal surface and a hydroxyapatitelayer disposed on at least part of the metal surface, the hydroxyapatitelayer comprising gallium ions therein, wherein the hydroxyapatite layercontinuously dissolves for more than 2 hours in vitro.

5. An orthopedic implant comprising a metal surface and a hydroxyapatitelayer disposed on at least part of the metal surface, the hydroxyapatitelayer comprising gallium ions therein, wherein the hydroxyapatite layeris substantially free of carbonate as measured by infrared spectroscopy.

6. The orthopedic implant of any one of the preceding clauses, whereinthe gallium ions are substituted into the crystal lattice of thehydroxyapatite layer.

7. The orthopedic implant of any one of the preceding clauses, whereinthe hydroxyapatite layer, when subjected to XRD, produces a (002) XRDpeak that is shifted by about 0.001° 2θ to about 0.1° 2θ compared to the(002) XRD peak of crystalline hydroxyapatite without gallium.

8. The orthopedic implant of any one of the preceding clauses, whereinthe hydroxyapatite layer, when subjected to XRD, produces a (002) XRDpeak that corresponds to a d-spacing shift of about 0.001 Å to about0.05 Å compared to the (002) XRD peak of crystalline hydroxyapatitewithout gallium.

9. The orthopedic implant of any one of the preceding clauses, whereinthe gallium ions comprise about 0.01 wt % to about 5 wt % of thehydroxyapatite layer.

10. The orthopedic implant of any one of the preceding clauses, whereinthe hydroxyapatite layer has an average crystallite size of less thanabout 75 nm in the direction.

11. The orthopedic implant of any one of the preceding clauses, whereinthe hydroxyapatite layer has an average crystallite size of about 10 toabout 75 nm in the direction.

12. The orthopedic implant of any one of the preceding clauses, whereinthe hydroxyapatite layer has an average crystallite size of about 20 nmto about 70 nm in the [001] direction.

13. The orthopedic implant of any one of the preceding clauses, whereinthe hydroxyapatite layer, when subjected to XRD, produces a (002) XRDpeak and a (112) XRD peak, and the (002) XRD peak has an intensity 1.5to 10 times greater than the (112) XRD peak.

14. The orthopedic implant of any one of the preceding clauses, whereinthe hydroxyapatite layer, when subjected to XRD, produces a (002) XRDpeak and a (112) XRD peak, and the (002) XRD peak has an intensity 2 to5 times greater than the (112) XRD peak.

15. The orthopedic implant of any one of the preceding clauses, whereinthe hydroxyapatite layer dissolves for more than 2 hours in vitro.

16. The orthopedic implant of any one of the preceding clauses, whereinthe hydroxyapatite layer dissolves for more than 5 hours in vitro.

17. The orthopedic implant of any one of the preceding clauses, whereinthe hydroxyapatite layer dissolves for more than 24 hours in vitro.

18. The orthopedic implant of any one of the preceding clauses, whereinthe hydroxyapatite layer is resorbed in vivo within 6 weeks.

19. The orthopedic implant of any one of the preceding clauses, whereinthe hydroxyapatite layer comprises about 0 wt % to about 5 wt %carbonate.

20. The orthopedic implant of any one of the preceding clauses, whereinthe hydroxyapatite layer is substantially free of carbonate as measuredby infrared spectroscopy.

21. The orthopedic implant of any one of the preceding clauses, whereinthe hydroxyapatite layer is in contact with the metal surface.

22. The orthopedic implant of any one of the preceding clauses, whereinthe metal surface comprises a metal oxide.

23. The orthopedic implant of any one of the preceding clauses, whereinthe metal surface comprises titanium.

24. The orthopedic implant of any one of the preceding clauses, whereinthe metal surface comprises a cobalt chromium alloy.

25. The orthopedic implant of any one of the preceding clauses, whereinthe metal surface comprises a titanium oxide.

26. The orthopedic implant of any one of the preceding clauses, whereinthe metal surface comprises a titanate.

27. The orthopedic implant of any one of the preceding clauses, whereinthe metal surface comprises sodium titanate.

28. The orthopedic implant of any one of the preceding clauses, whereinthe metal surface is a porous metal oxide surface.

29. The orthopedic implant of any one of the preceding clauses, whereinthe metal surface is a titanium surface that has been treated withhydroxide.

30. The orthopedic implant of clause 29, wherein the hydroxide has aconcentration of 1M or greater.

31. The orthopedic implant of clause 29 or 30, wherein the hydroxide hasa concentration of 2M or greater.

32. The orthopedic implant of any one of clauses 29 to 31, wherein thehydroxide is sodium hydroxide.

33. The orthopedic implant of any one of clauses 29 to 32, wherein thehydroxide is potassium hydroxide.

34. The orthopedic implant of any one of clauses 29 to 33, wherein thetitanium surface is not heat treated after being treated with thehydroxide.

35. The orthopedic implant of any one of the preceding clauses, whereinthe metal surface has a thickness greater than about 50 nm.

36. The orthopedic implant of any one of the preceding clauses, whereinthe metal surface has a thickness between about 50 nm and about 1 μm.

37. The orthopedic implant of any one of the preceding clauses, whereinthe metal surface has a thickness between about 50 nm and about 100 nm.

38. The orthopedic implant of any one of the preceding clauses, whereinthe hydroxyapatite layer has a crystallinity of greater than about 90%.

39. The orthopedic implant of any one of the preceding clauses, whereinthe hydroxyapatite layer has a crystallinity of about 70 wt % to about100 wt %.

40. The orthopedic implant of any one of the preceding clauses, whereinthe hydroxyapatite layer has a phase purity of crystallinehydroxyapatite of greater than 90%.

41. The orthopedic implant of any one of the preceding clauses, whereinthe hydroxyapatite layer has a shear strength of about 20 MPa to about80 MPa as determined according to ASTM F1044.

42. The orthopedic implant of any one of the preceding clauses, whereinthe hydroxyapatite layer has a tensile strength of about 50 MPa to about100 MPa as determined according to ASTM F1147.

43. The orthopedic implant of any one of the preceding clauses, whereinthe hydroxyapatite layer, in the absence of colorants, is transparent ortranslucent.

44. The orthopedic implant of any one of the preceding clauses, whereinthe hydroxyapatite layer has a Ca/P ratio of 1 to 2.

45. The orthopedic implant of any one of the preceding clauses, whereinthe hydroxyapatite layer has a surface area of about 15 m²/g to about200 m²/g.

46. The orthopedic implant of any one of the preceding clauses, whereinthe hydroxyapatite layer does not release particulates underphysiological conditions.

47. The orthopedic implant of any one of the preceding clauses, whereinthe hydroxyapatite layer is a calcium-deficient hydroxyapatite layer.

48. The orthopedic implant of any one of the preceding clauses, whereingallium is distributed throughout the hydroxyapatite layer.

49. A method of treating a patient comprising administering to thepatient the orthopedic implant of any one of the preceding clauses.

Additionally, several embodiments of the invention are described by thefollowing enumerated clauses:

1. An osteoconductive composition comprising hydroxyapatite, thehydroxyapatite comprising gallium ions therein, wherein thehydroxyapatite is crystalline.

2. An osteoconductive composition comprising hydroxyapatite, thehydroxyapatite comprising gallium ions therein, wherein thehydroxyapatite has an average crystallite size of less than about 75 nmin the [001] direction.

3. An osteoconductive composition comprising hydroxyapatite, thehydroxyapatite comprising gallium ions therein, wherein thehydroxyapatite, when subjected to XRD, produces a (002) XRD peak and a(112) XRD peak, and the (002) XRD peak has an intensity 1.5 to 10 timesgreater than the (112) XRD peak.

4. An osteoconductive composition comprising hydroxyapatite, thehydroxyapatite comprising gallium ions therein, wherein thehydroxyapatite continuously dissolves for more than 2 hours in vitro.

5. An osteoconductive composition comprising hydroxyapatite, thehydroxyapatite comprising gallium ions therein, wherein thehydroxyapatite is substantially free of carbonate as measured byinfrared spectroscopy.

6. The osteoconductive composition of any one of the preceding clauses,wherein the gallium ions are substituted into the crystal lattice of thehydroxyapatite.

7. The osteoconductive composition of any one of the preceding clauses,wherein the hydroxyapatite, when subjected to XRD, produces a (002) XRDpeak that is shifted by about 0.001° 2θ to about 0.1° 2θ compared to the(002) XRD peak of crystalline hydroxyapatite without gallium.

8. The osteoconductive composition of any one of the preceding clauses,wherein the hydroxyapatite, when subjected to XRD, produces a (002) XRDpeak that corresponds to a d-spacing shift of about 0.001 Å to about0.05 Å compared to the (002) XRD peak of crystalline hydroxyapatitewithout gallium.

9. The osteoconductive composition of any one of the preceding clauses,wherein the gallium ions comprise about 0.01 wt % to about 5 wt % of thehydroxyapatite.

10. The osteoconductive composition of any one of the preceding clauses,wherein the hydroxyapatite has an average crystallite size of less thanabout 75 nm in the direction.

11. The osteoconductive composition of any one of the preceding clauses,wherein the hydroxyapatite has an average crystallite size of about 10to about 75 nm in the [001] direction.

12. The osteoconductive composition of any one of the preceding clauses,wherein the hydroxyapatite has an average crystallite size of about 20nm to about 70 nm in the [001] direction.

13. The osteoconductive composition of any one of the preceding clauses,wherein the hydroxyapatite, when subjected to XRD, produces a (002) XRDpeak and a (112) XRD peak, and the (002) XRD peak has an intensity 1.5to 10 times greater than the (112) XRD peak.

14. The osteoconductive composition of any one of the preceding clauses,wherein the hydroxyapatite, when subjected to XRD, produces a (002) XRDpeak and a (112) XRD peak, and the (002) XRD peak has an intensity 2 to5 times greater than the (112) XRD peak.

15. The osteoconductive composition of any one of the preceding clauses,wherein the hydroxyapatite dissolves for more than 2 hours in vitro.

16. The osteoconductive composition of any one of the preceding clauses,wherein the hydroxyapatite dissolves for more than 5 hours in vitro.

17. The osteoconductive composition of any one of the preceding clauses,wherein the hydroxyapatite dissolves for more than 24 hours in vitro.

18. The osteoconductive composition of any one of the preceding clauses,wherein the hydroxyapatite is resorbed in vivo within 6 weeks.

19. The osteoconductive composition of any one of the preceding clauses,wherein the hydroxyapatite comprises about 0 wt % to about 5 wt %carbonate.

20. The osteoconductive composition of any one of the preceding clauses,wherein the hydroxyapatite is substantially free of carbonate asmeasured by infrared spectroscopy.

21. The osteoconductive composition of any one of the preceding clauses,wherein the hydroxyapatite is in contact with a metal surface.

22. The osteoconductive composition of clause 21, wherein the metalsurface comprises a metal oxide.

23. The osteoconductive composition of clause 21 or 22, wherein themetal surface comprises titanium.

24. The osteoconductive composition of clause 21 or 23, wherein themetal surface comprises a cobalt chromium alloy.

25. The osteoconductive composition of any one of clauses 21 to 24,wherein the metal surface comprises a titanium oxide.

26. The osteoconductive composition of any one of clauses 21 to 25,wherein the metal surface comprises a titanate.

27. The osteoconductive composition of any one of clauses 21 to 26,wherein the metal surface comprises sodium titanate.

28. The osteoconductive composition of any one of clauses 21 to 27,wherein the metal surface is a porous metal oxide surface.

29. The osteoconductive composition of any one of clauses 21 to 28,wherein the metal surface is a titanium surface that has been treatedwith hydroxide.

30. The osteoconductive composition of clause 29, wherein the hydroxidehas a concentration of 1M or greater.

31. The osteoconductive composition of clause 29 or 30, wherein thehydroxide has a concentration of 2M or greater.

32. The osteoconductive composition of any one of clauses 29 to 31,wherein the hydroxide is sodium hydroxide.

33. The osteoconductive composition of any one of clauses 29 to 32,wherein the hydroxide is potassium hydroxide.

34. The osteoconductive composition of any one of clauses 29 to 33,wherein the titanium surface is not heat treated after being treatedwith the hydroxide.

35. The osteoconductive composition of any one of clauses 29 to 34,wherein the metal surface has a thickness greater than about 50 nm.

36. The osteoconductive composition of any one of clauses 29 to 35,wherein the metal surface has a thickness between about 50 nm and about1 μm.

37. The osteoconductive composition of any one of clauses 29 to 36,wherein the metal surface has a thickness between about 50 nm and about100 nm.

38. The osteoconductive composition of any one of the preceding clauses,wherein the hydroxyapatite has a crystallinity of greater than about90%.

39. The osteoconductive composition of any one of the preceding clauses,wherein the hydroxyapatite has a crystallinity of about 70 wt % to about100 wt %.

40. The osteoconductive composition of any one of the preceding clauses,wherein the hydroxyapatite has a phase purity of crystallinehydroxyapatite of greater than 90%.

41. The osteoconductive composition of any one of the preceding clauses,wherein the hydroxyapatite has a shear strength of about 20 MPa to about80 MPa as determined according to ASTM F1044.

42. The osteoconductive composition of any one of the preceding clauses,wherein the hydroxyapatite has a tensile strength of about 50 MPa toabout 100 MPa as determined according to ASTM F1147.

43. The osteoconductive composition of any one of the preceding clauses,wherein the hydroxyapatite, in the absence of colorants, is transparentor translucent.

44. The osteoconductive composition of any one of the preceding clauses,wherein the hydroxyapatite has a Ca/P ratio of 1 to 2.

45. The osteoconductive composition of any one of the preceding clauses,wherein the hydroxyapatite has a surface area of about 15 m²/g to about200 m²/g.

46. The osteoconductive composition of any one of the preceding clauses,wherein the hydroxyapatite does not release particulates underphysiological conditions.

47. The osteoconductive composition of any one of the preceding clauses,wherein the hydroxyapatite is calcium-deficient hydroxyapatite.

48. The osteoconductive composition of any one of the preceding clauses,wherein gallium is distributed throughout the hydroxyapatite.

Additionally, several embodiments of the invention are described by thefollowing enumerated clauses:

1. A method of forming a hydroxyapatite coating, the method comprisingcontacting a metal surface with a supersaturated solution comprisingcalcium ions, phosphate ions, and gallium ions and reducing the amountof air in contact with the supersaturated solution during the coatingstep.

2. A method of forming a hydroxyapatite coating, the method comprisingcontacting a metal surface with a supersaturated solution comprisingcalcium ions, phosphate ions, and gallium ions wherein the pH of thesolution varies by less than 0.1 pH unit/hour during the contactingstep.

3. A method of forming a hydroxyapatite coating, the method comprisingcontacting a metal surface with a supersaturated solution comprisingcalcium ions, phosphate ions, and gallium ions wherein hydroxyapatiteforms on the metal surface at a rate of 0.05 μm/h to 1.5 μm/h.

4. A method of forming a hydroxyapatite coating, the method comprisingmixing a first solution comprising gallium ions and phosphate ions and asecond solution comprising calcium ions to form a supersaturatedsolution and contacting a metal surface with the supersaturatedsolution.

5. The method of any one of the preceding clauses, wherein the metalsurface is a metal oxide surface.

6. The method of any one of the preceding clauses, wherein thehydroxyapatite coating is formed on an orthopedic implant comprising themetal surface.

7. The method of any one of the preceding clauses, further comprisingreducing the amount of air in contact with the supersaturated solutionduring the coating step.

8. The method of any one of the preceding clauses, wherein the pH of thesupersaturated solution varies by less than 0.1 pH unit/hour during thecontacting step.

9. The method of any one of the preceding clauses, further comprisingallowing the pH to decrease during the contacting step by apredetermined value that is less than 0.15 pH units.

10. The method of any one of the preceding clauses, whereinhydroxyapatite forms on the metal surface at a rate of 0.05 μm/h to 1μm/h.

11. The method of any one of the preceding clauses, wherein thehydroxyapatite coating is a calcium-deficient hydroxyapatite coating.

12. The method of any one of the preceding clauses, wherein the pH ofthe supersaturated solution is from about 7.5 to about 7.9.

13. The method of any one of the preceding clauses, wherein theconcentration of calcium in the supersaturated solution is from about1.4 mM to about 1.8 mM.

14. The method of any one of the preceding clauses, wherein theconcentration of phosphate in the supersaturated solution is from about2 mM to about 2.3 mM.

15. The method of any one of the preceding clauses, wherein theconcentration of gallium in the supersaturated solution is from about0.01 mM to about 1.0 mM.

16. The method of any one of the preceding clauses, wherein the Gibbsfree energy change associated with forming the hydroxyapatite coating isfrom about 8 kJ/mol to about 8.4 kJ/mol when the contacting step begins.

17. The method of any one of the preceding clauses, wherein the coatingforms at a rate per unit surface area from about 0.015 mg/hr·mm² to 0.05about mg/hr·mm².

18. The method of any one of the preceding clauses, further comprisingremoving the metal surface from the supersaturated solution after fromabout 0.5 hour to about 12 hours.

19. The method of clause 18, further comprising contacting the metalsurface, after the removing step, with an additional amount of thesupersaturated solution that has not contacted the metal surface.

20. The method of any one of the preceding clauses, wherein thetemperature of the supersaturated solution is from about 45° C. to about50° C.

21. The method of any one of the preceding clauses, wherein thetemperature of the supersaturated solution is from about 46.5° C. to47.5° C.

22. The method of any one of the preceding clauses, wherein thesupersaturated solution further comprises a salt and a buffer.

23. The method of clause 22, wherein the salt is sodium chloride and thebuffer is tris(hydroxymethyl)aminomethane.

24. The method of any one of the preceding clauses, further comprisingagitating the supersaturated solution during the contacting step.

25. The method of any one of the preceding clauses, whereinheterogeneous crystal growth occurs on the metal surface and homogeneouscrystal growth does not occur.

26. The method of any one of the preceding clauses, further comprisingforming a titanium layer on an implant body to form the metal surface.

27. The method of any one of the preceding clauses, further comprisingactivating the metal surface by contacting the metal surface with abase.

28. The method of clause 27, wherein the base is a hydroxide anion.

29. The method of any one of the preceding clauses, wherein the metalsurface is a titanium dioxide surface.

30. The method of any one of the preceding clauses, wherein the metalsurface is an activated metal surface.

31. The method of any one of the preceding clauses, wherein the metalsurface comprises a titanate.

32. The method any one of the preceding clauses, wherein the processoccurs under inert atmospheric conditions.

33. The method of any one of the preceding clauses, wherein the processoccurs under an argon atmosphere.

34. The method of any one of the preceding clauses, wherein a firstsolution comprising gallium ions and phosphate ions and a secondsolution comprising calcium ions are mixed at from about 15° C. to about35° C.

35. The method of any one of the preceding clauses, wherein thehydroxyapatite coating is not further treated to increase crystallinityafter the contacting step.

36. The method of any one of the preceding clauses, wherein the methodis validated for the amount of the calcium phosphate coating on themetal surface.

37. The method of any one of the preceding clauses, wherein thehydroxyapatite coating is formed predominantly through heterogeneousnucleation such that the supersaturated solution remains visibly free ofturbidity during the contacting step.

38. The method of any one of the preceding clauses, wherein thehydroxyapatite coating forms at a substantially continuous ratethroughout the contacting step.

39. The method of any one of the preceding clauses, further comprisingdetermining the amount of the hydroxyapatite coating based on theamounts of the calcium ions and the phosphate ions.

40. The method of any one of the preceding clauses, wherein at least twodeposition sequences are employed.

41. The method of any one of the preceding clauses, further comprisingdetermining the amount of the hydroxyapatite coating based on the pH ofthe supersaturated solution.

42. The method of any one of the preceding clauses, further comprisingdetermining the amount of the hydroxyapatite coating based on theduration of the contacting step.

43. The method of any one of the preceding clauses, wherein the pH ofthe supersaturated solution varies by from about 0.01 to about 0.1 pHunit/hour during the contacting step.

44. The method of any one of the preceding clauses, wherein the coatingforms at a rate per unit surface area from about 0.005 mg/hr·mm² to0.015 about mg/hr·mm².

45. The method of any one of the preceding clauses, wherein the initialpH of the supersaturated solution is from about 7.5 to about 7.9, andthe temperature of the supersaturated solution is from about 38° C. toabout 60° C.

46. The method of any one of the preceding clauses, further comprisingheating the coating in a phosphate solution to mitigate surfacecracking.

47. The method of any one of the preceding clauses, further comprisingcontacting the coating with a supercritical fluid to mitigate surfacecracking.

48. An osteoconductive composition formed according to the method of anyone of the preceding clauses.

49. An orthopedic implant comprising an osteoconductive compositionformed according to the method of any one of the preceding clauses.

The above and other objects, features, and advantages of the presentinvention will become apparent from the following description and theattached drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a chart showing the weights of hydroxyapatite coatings formedon crystalline and amorphous 50 nm- to 500 nm-thick titanium dioxide(TiO₂) coated substrates;

FIG. 2 is a scanning electron microscopy (SEM) image of a 200 nm-thickamorphous TiO₂ coating after treatment with hydroxide;

FIG. 3 is an SEM image of a 200 nm-thick crystalline TiO₂ coating thatwas not treated with hydroxide;

FIG. 4 is a grazing angle X-ray diffraction (XRD) spectrum overlay,showing spectra for 200 nm-thick amorphous TiO₂ coatings, with andwithout hydroxide treatment, and 500 nm-thick amorphous TiO₂ coatings,with and without hydroxide treatment;

FIG. 5 is a grazing angle XRD spectrum overlay, showing spectra for 200nm-thick crystalline TiO₂ coatings, with and without hydroxidetreatment, and 500 nm-thick crystalline TiO₂ coatings, with and withouthydroxide treatment;

FIG. 6 is an SEM image of a titanium layer that has beenelectrodeposited onto a CoCrMo core;

FIG. 7 is an image of a full scale coating vessel;

FIG. 8 is an SEM image of a SoDHA coating at 15000× magnification;

FIG. 9A is an SEM image of a SoDHA coating at 100× magnification;

FIG. 9B is an SEM image of a SoDHA coating at 400× magnification;

FIG. 10 is a chart showing a relationship between pH and the weight ofhydroxyapatite precipitate precipitate over the course of theirrespective deposition processes;

FIG. 11 is a chart showing deposition rates at different surface areasfor a solution deposited hydroxyapatite (SoDHA) process;

FIG. 12 is a chart showing the Ca/P ratios of five samples createdaccording to the SoDHA process in the full scale deposition system shownin FIG. 7;

FIG. 13 is a chart showing the crystallinity of the hydroxyapatite inthe five samples described in FIG. 12;

FIG. 14 is a chart showing the percentage of crystalline hydroxyapatitein the materials formed by the SoDHA process in the five samplesdescribed in FIG. 12;

FIG. 15 is a chart showing the tensile strength of the hydroxyapatite inthe five samples described in FIG. 12;

FIG. 16 is a chart showing the shear strength of the hydroxyapatite inthe five samples described in FIG. 12;

FIG. 17 shows a hip stem coupon fixture used in the XRD characterizationstudy described herein;

FIG. 18 shows superimposed XRD scans for as coated gallium-substitutedSoDHA HA discs for 0 wt % to 20 wt % Ga solution conditions;

FIG. 19 shows 25° to 27° 2θ of the superimposed XRD scans of FIG. 18;

FIG. 20 shows % Ga in gallium-substituted SoDHA HA discs formed at 0 wt.% to 20 wt. % Ga solution conditions;

FIG. 21 shows a Fourier transform infrared spectroscopy (FTIR) spectrumof a scraped SoDHA-G HA powder;

FIG. 22 is a chart showing the dissolution rate of a gallium-substitutedSoDHA HA sample;

FIG. 23 is a chart showing the dissolution rate of a National Instituteof Standards and Technology (NIST) standard HA sample;

FIG. 24 shows DSC traces from scraped SoDHA powders showing nodiscernible exothermic peaks on heating;

FIG. 25 shows bone ingrowth for implants having SoDHA andgallium-substituted SoDHA coatings in a canine model;

FIG. 26A is an SEM image of an air-dried gallium-substituted SoDHAcoating without post-processing at 400× magnification;

FIG. 26B is an SEM image of a scCO₂-dried gallium-substituted SoDHAcoating at 400× magnification;

FIG. 27 is an SEM image of an oven-dried gallium-substituted SoDHAcoating at 400× magnification;

FIG. 28A is an SEM image of gallium-substituted SoDHA coating afterhydrothermally treated at 70° C. for 2 hours in phosphate-Ga stock at800× magnification;

FIG. 28B is an SEM image of gallium-substituted SoDHA coating afterhydrothermally treated at 70° C. for 2 hours in phosphate-Ga syrup at1000× magnification;

FIG. 29A is an SEM image of gallium-substituted SoDHA coating afterhydrothermally treated at 90° C. for 1 hour in phosphate-Ga stock at501× magnification;

FIG. 29B is an SEM image of gallium-substituted SoDHA coating afterhydrothermally treated at 90° C. for 1 hour in phosphate-Ga syrup at500× magnification;

FIG. 30A is an SEM image of gallium-substituted SoDHA coating afterhydrothermally treated at 90° C. for 2 hours in phosphate-Ga stock at500× magnification;

FIG. 30B is an SEM image of gallium-substituted SoDHA coating afterhydrothermally treated at 90° C. for 2 hours in phosphate-Ga syrup at500× magnification;

FIG. 31 superimposed XRD scans of a SoDHA coating withoutpost-processing, a gallium-substituted SoDHA coating withoutpost-processing, and a hydrothermally treated gallium substituted SoDHAcoating; and

FIG. 32 shows representative images illustrating a crack densityquantification method.

DETAILED DESCRIPTION OF THE ILLUSTRATIVE EMBODIMENTS

While the invention is susceptible to various modifications andalternative forms, specific embodiments thereof have been shown by wayof example in the drawings and will herein be described in detail. Itshould be understood, however, that there is no intent to limit theinvention to the particular forms disclosed, but on the contrary, theintention is to cover all modifications, equivalents, and alternativesfalling within the spirit and scope of the invention as defined by theappended claims.

The present invention relates to calcium phosphate coated orthopedicimplants, such as gallium-substituted hydroxyapatite (HA) coatedorthopedic implants, and methods of making the same. Without intendingto be bound by theory, the presence of gallium in the coatings isbelieved to allow for enhanced biocompatibility compared to traditionalhydroxyapatite coatings. In the present invention, gallium ions (Ga⁺³)are incorporated or doped into an hydroxyapatite (HA) lattice, thusallowing for the localized controlled release of this therapeutic ion asthe HA coating resorbs over several weeks in vivo. Gallium mayaccumulate in newly formed bone, aid in new bone formation,down-regulate inflammation as well as possess anti-bacterial activity.The gallium-substituted HA coatings described herein may be used inmultifunctional coatings for enhancing osteogenic potential at the siteof implantation and promoting anti-bacterial efficacy.

The gallium-substituted hydroxyapatite coatings described herein have ahighly uniform microstructure. When the implants are used in a human oranimal, the gallium-substituted hydroxyapatite coating degradesuniformly over an extended period of time without releasingparticulates. In some embodiments, this is a period of 6 weeks or less.The coatings described herein also have advantageous adhesion and/orcohesion properties such as increased tensile strength compared to priorcoatings. Additionally, the gallium-substituted hydroxyapatite coatingsdescribed herein can be rapidly formed on a substrate by a controlled,but rapid, growth process that lends itself to process validationutilizing process diagnostics that allow determination of total coatingweight on a batch of parts without having to measure coating weights onparts resulting in the coatings' uniform microstructures and chemicalcompositions.

Solution deposited ceramic coatings may be predisposed to crackingduring drying. As coating thickness is increased this effect may beexacerbated. In some instances, cracking may be observed for solutiondeposited gallium-substituted SoDHA (SoDHA-G) coatings as they are driedafter being formed. Without intending to be bound by theory, compared toSoDHA coatings without gallium, SoDHA-G coatings exhibit a greaterpropensity for cracking and this could potentially be a result oflattice strain that accompanys doping gallium into the hydroxyapatitelattice. Two exemplary, independent methods to mitigate drying cracksthat are described herein include: (1) organic solvent exchange andsupercritical solvent extraction, and (2) re-precipitation crack healingvia hydrothermal treatment. It is to be understood that organic solventexchange and re-precipitation crack healing may be performed independentof each other or in combination.

The compositions and methods described herein may improve cementlessfixation of orthopedic implants for improved survivorship and expand useof cementless implants to procedures where cemented implants are thecurrent standard of care. One skilled in the art understands that thismay allow for reduced operating room time and decreased costs for healthcare.

Gallium-Substituted Hydroxyapatite Coating

The calcium phosphate coatings described herein comprisegallium-substituted HA. As used herein, HA includes but is not limitedto calcium deficient hydroxyapatite (CDHA) where calcium ions have beensubstituted by gallium. In some embodiments, the HA described herein isnon-stoichiometric, gallium substituted HA. The gallium-substituted HAmay be of the formula Ca_(10-x)Ga_(x)(PO₄)₆(OH)_(2-x)(CO₃)_(x), whereinx is from about 0 to about 1 or about 0.1 to about 1. It is to beunderstood that the formulas described herein describe stoichiometricequivalents. The HA coatings have characteristic molar ratios of calciumto phosphate (Ca/P ratio). The Ca/P ratio may be from about 1 to about2, about 1.2 to about 2, about 1.3 to about 2, about 1.39 to about 2,about 1 to about 1.8, about 1.2 to about 1.8, about 1.3 to about 1.8,about 1.39 to about 1.8, about 1 to about 1.7, about 1.2 to about 1.7,about 1.3 to about 1.7, about 1.39 to about 1.7, about 1 to about 1.649,about 1.2 to about 1.649, about 1.3 to about 1.649, about 1.39 to about1.649, or about 1.5 to about 1.67. It is to be understood that thegallium-substituted HA may be modified by adjusting calcium andphosphate concentrations in the solutions from which the HA coatings maybe formed.

In the gallium-substituted HA coatings, some of the calcium ions aresubstituted by gallium ions, compared to traditional HA. The bioactivegallium-substituted hydroxyapatite coating produced herein desirablycontains a molar ratio of gallium ions to calcium ions of about 1:10 toabout 1:5000, about 1:10 to about 1:1500, or about 1:20 to about 1:1500.Accordingly, the Ca/P ratios can be altered as a function of Gasubstitution into the hydroxyapatite lattice.

As further described below, the gallium-substituted HA coatings areformable from supersaturated solutions that remain substantially free ofturbidity, due to homogenous nucleation in solution, throughout thecoating process. In some embodiments, the gallium-substituted HAcoatings lack carbonate, which assists with pH control during coatingformation. Without intending to be bound by theory, deposition fromsolutions substantially free of turbidity due to homogenous nucleationis believed to play a role in gallium-substituted HA coatings depositedwith predictable coating rates and gallium-substituted HA having highcrystallinity, uniform microstructure, and enhanced biocompatibility. Insome embodiments, the wt. % carbonate in the coatings is about 0% toabout 25%, about 0% to about 20%, about 0% to about 15%, about 0% toabout 10%, about 0% to about 5%, about 0% to about 3%, about 0% to about2%, about 0% to about 1%, about 0% to about 0.1%, about 0.1% to about25%, about 0.1% to about 20%, about 0.1% to about 15%, about 0.1% toabout 10%, about 0.1% to about 5%, about 0.1% to about 3%, about 0.1% toabout 2%, about 0.1% to about 1%, about 1% to about 25%, about 1% toabout 20%, about 1% to about 15%, about 1% to about 10%, about 1% toabout 5%, about 1% to about 3%, about 1% to about 2%, about 2% to about25%, about 2% to about 20%, about 2% to about 15%, about 2% to about10%, about 2% to about 5%, or about 2% to about 3%. In some embodiments,the concentration of carbonate in the coatings is as measured byspectroscopic methods such as IR spectroscopy. The coatings may besubstantially carbonate-free. As used herein, “substantiallycarbonate-free” coatings refers to coatings that do not have adistinguishable carbonate peak between 1500 cm⁻¹ and 1300 cm⁻¹ whensubjected to IR spectroscopy.

The wt % of crystalline gallium-substituted HA in the coatings describedherein is about 50% to about 100%, about 60% to about 100%, about 70% toabout 100%, about 80% to about 100%, about 90% to about 100%, about 50%to about 99%, about 60% to about 99%, about 70% to about 99%, about 80%to about 99%, about 90% to about 99%, about 50% to about 95%, about 60%to about 95%, about 70% to about 95%, about 80% to about 95%, or about90% to about 95%. Without intending to be bound by theory, it isbelieved that the coatings are formed by heterogeneous nucleation,resulting in coatings that primarily comprise crystallinegallium-substituted HA or OCP.

The gallium-substituted HA component of the gallium-substituted HAcoatings has a high crystallinity as measured by, for example,differential scanning calorimetry (DSC). The crystallinity is greaterthan about 50%, greater than about 80%, greater than about 90%, greaterthan about 95%, greater than about 96%, greater than about 97%, about80% to about 99.9%, about 90% to about 99.9%, about 95% to about 99.9%,about 96% to about 99.9%, or about 97% to about 99.9%.

The gallium-substituted HA component of the coatings has a highcrystalline phase purity of its predominant phase. The crystalline phasepurity is greater than about 80%, greater than about 90%, greater thanabout 95%, greater than about 96%, greater than about 97%, about 80% toabout 99.9%, about 90% to about 99.9%, about 95% to about 99.9%, about96% to about 99.9%, or about 97% to about 99.9%. The high crystallinityand high crystalline phase purity of the gallium-substituted HAcomponent in the gallium-substituted HA coatings enhancesbiocompatibility and homogenous degradation in vivo while avoidingparticulate release. In some embodiments, crystallinity is measured bydifferential scanning calorimetry (DSC).

The gallium-substituted HA component of the coatings has low or noamorphous content. The amorphous content is less than about 20%, lessthan about 15%, less than about 10%, less than about 5%, less than about4%, less than about 3%, about 0.1% to about 3%, about 0.1% to about 5%,about 0.1% to about 10%, or about 0.1% to about 20%. The amorphouscontent may be too low to detect. In some embodiments, amorphous contentis measured by differential scanning calorimetry (DSC).

The crystal structure of the gallium-substituted HA coatings can becharacterized using X-ray spectroscopy, such as X-ray powder diffractionspectroscopy. The gallium-substituted HA coatings exhibit severalcharacteristic 20 diffraction angles when characterized by X-ray powderdiffraction. The numbers shown in parenthesis are the Miller indicesassociated with each peak. The X-ray spectra of the gallium-substitutedHA coatings may exhibit 2θ diffraction angles including about 26±2°(002), about 28±2° (102), about 32±2° (112), about 50±2° (213), andabout 53±2° (004) or 26±0.5° (002), about 28±0.5° (102), about 32±0.5°(112), about 50±0.5° (213), and about 53±0.5° (004). The X-ray spectraof the gallium-substituted HA coatings may exhibit 2θ diffraction anglesincluding about 26±1° (002), about 28±1° (102), about 32±1° (112), about50±1° (213), and about 53±1° (004). The X-ray spectra of thegallium-substituted HA coatings may exhibit 2θ diffraction anglesincluding about 25.58±0.1°, about 28.13±0.1°, about 31.75±0.1°,32.17±0.1°, about 49±0.1°, and about 53±0.1°. It is to be understoodthat the diffraction angles recited herein may be systematically shifteddue to variations in instrumentation.

The XRD spectra of the gallium-substituted HA coatings havecharacteristic relative intensities. As used herein, the relativeintensity of a peak in an XRD spectrum refers to the intensity of a peakdivided by the intensity of the most intense peak in the spectrum. Thepeaks associated with the (002), (211), (112), (202), (213), and (004)directions may have relative intensities of 100%, 40-50%, 45-55%,15-25%, 10-20%, and 15-25%, respectively. Any one of the peaksassociated with the (002), (211), (112), (202), (213), and (004)directions may have a relative intensity of 100%, 30-60%, 35-65%, 5-35%,0-30%, and 5-35%, respectively. In some embodiments, the hydroxyapatitelayer has a ratio of XRD intensity ratio of the (002) peak: the (211)peak that is greater than about 1, greater than about 1.25, greater thanabout 1.5, greater than about 1.75, greater than about 2.0, greater thanabout 2.5, greater than about 3.0, or greater than about 3.5.

As a result of gallium substitution, the 2θ diffraction angle of the(002) peak is shifted compared to a HA coating formed by the solutiondeposited process without gallium when the coatings are characterizedusing X-ray spectroscopy. The resulting shift of the (002) diffractionpeak may be about up to about 0.25°, up to about 0.2°, up to about0.15°, about 0.01° to about 0.25°, about 0.01° to about 0.2°, about0.01° to about 0.15°, about 0.05° to about 0.25°, about 0.05° to about0.2°, or about 0.05° to about 0.15°. The shift of the (002) diffractionpeak may increase with increasing gallium ion concentration. The (002)diffraction peak 2θ shift is associated with a d-spacing shift rangingfrom about 0.001 Å to about 0.05 Å, about 0.0025 Å to about 0.025 Å, orabout 0.0037 Å to about 0.0226 Å.

The gallium-substituted HA coatings can also be characterized usingFourier transform infrared (FTIR) spectroscopy. The gallium-substitutedHA coatings exhibit FTIR bands at about 1100 cm⁻¹, characteristic of PO₄³⁻. The gallium-substituted HA coatings lack FTIR bands characteristicfor carbonate between about 1400 to 1500 cm⁻¹.

In some embodiments, the gallium-substituted HA coatings arenanocrystalline. Accordingly, gallium-substituted HA coatings of theinstant disclosure result in small crystallites sizes as determined byX-ray diffraction or scanning electron microscopy. Thegallium-substituted hydroxyapatite has an average crystallite sizeranging from about 1 nm to about 100 nm, about 5 nm to about 100 nm,about 10 nm to about 100 nm, about 15 nm to about 100 nm, about 1 nm toabout 80 nm, about 5 nm to about 80 nm, about 10 nm to about 80 nm,about 15 nm to about 80 nm, or about 15 nm to about 70 nm. The averagecrystallite size in the (002) direction is from about 60 nm to about 80nm, about 65 nm to about 75 nm, about 66 nm to about 73 nm, or about 68nm to about 69 nm. The average crystallite size in the (200) directionis from about 10 nm to about 30 nm, about 15 nm to about 25 nm, about 16nm to about 23 nm, or about 18 nm to about 22 nm. The averagecrystallite size in the (210) direction is from about 40 nm to about 60nm, about 45 nm to about 55 nm, about 46 nm to about 53 nm, or about 48nm to about 52 nm. In some embodiments, the gallium-substituted HA filmshave a crystallite size in at least one direction that is less than thewavelength of light, and the grains are bonded to one another withoutthe presence of a second amorphous or crystalline phase having adifferent refractive index. In such embodiments, the coatings aretransparent or translucent.

Gallium-substituted HA coatings of the instant disclosure are highlyporous and have high surface areas. The surface area is about 5 m²/g toabout 100 m²/g, about 10 m²/g to about 75 m²/g, about 10 m²/g to about50 m²/g, about 10 m²/g to about 200 m²/g, about 10 m²/g to about 150m²/g, about 10 m²/g to about 100 m²/g, about 50 m²/g to about 200 m²/g,about 50 m²/g to about 150 m²/g, about 50 m²/g to about 100 m²/g, orabout 15 m²/g to about 35 m²/g. The surface area may be determined usingBrunauer-Emmett-Teller (BET) method. This surface area may lead tosignificant improvements in adsorption of therapeutic agents onto thesecoatings, as further discussed below. The increased loading capabilitymay be utilized to tailor the dose and prolonged release of thetherapeutic agents thereby increasing treatment efficacy.

Without intending to be bound by theory, another benefit ofgallium-substituted HA crystallite size reduction may be in refining thesurface nano-topography of implant surfaces thereby increasingadsorption of fibrinogen from blood after implantation. Thissubsequently increases platelet adhesion and activation, which is aninitiator of the inflammatory cascade and healing process.Nano-topography has also shown to improve the adhesion strength of thefibrin clot (or extracellular matrix) to the implant surface therebyensuring its integrity during new bone formation and wound contractionthroughout the healing process.

The coatings described herein may release calcium and/or gallium at asubstantially continuous rate or at a continuous rate over an extendedperiod of time in vitro as measured by calcium electrodes as describedin ASTM F1926. As used herein, a substantially continuous rate is a ratethat changes by less than 20% each hour. As used herein, a continuousrate is a rate that changes by less than 5% each hour. The coatings mayrelease calcium at a substantially continuous rate for at least about 5hours, at least about 10 hours, at least about 15 hours, at least about20 hours, about 5 hours to about 100 hours, about 5 hours to about 50hours, about 5 hours to about 30 hours, about 5 hours to about 25 hours,about 10 hours to about 100 hours, about 10 hours to about 50 hours,about 10 hours to about 30 hours, about 10 hours to about 25 hours,about 15 hours to about 100 hours, about 15 hours to about 50 hours,about 15 hours to about 30 hours, or about 15 hours to about 25 hours.The coatings may release calcium at a continuous rate for at least about5 hours, at least about 10 hours, at least about 15 hours, at leastabout 20 hours, about 5 hours to about 100 hours, about 5 hours to about50 hours, about 5 hours to about 30 hours, about 5 hours to about 25hours, about 10 hours to about 100 hours, about 10 hours to about 50hours, about 10 hours to about 30 hours, about 10 hours to about 25hours, about 15 hours to about 100 hours, about 15 hours to about 50hours, about 15 hours to about 30 hours, or about 15 hours to about 25hours.

The gallium-substituted HA coatings described herein may have highadhesion to a substrate and have high cohesion compared to previouslydescribed coatings. Adhesion and cohesion can be quantified by measuringtensile and shear peak stress values. The coatings described hereinextend outward from a surface of an orthopedic implant. As used herein,shear stress is the stress component parallel to the bulk directionsurface, and tensile stress is the stress component away from the bulkdirection surface.

The shear peak stress of the gallium-substituted HA coatings, asdetermined according to ASTM F1044, may be about 10 MPa to about 150MPa, about 10 MPa to about 100 MPa, about 10 MPa to about 75 MPa, about10 MPa to about 65 MPa, or about 28.2 MPa to about 63.6 MPa. The tensilepeak stress, as determined according to ASTM F1147, may be about 25 MPato about 120 MPa, about 40 MPa to about 120 MPa, about 50 MPa to about120 MPa, about 60 MPa to about 120 MPa, about 68 MPa to about 120 MPa,25 MPa to about 100 MPa, about 40 MPa to about 100 MPa, about 50 MPa toabout 100 MPa, about 60 MPa to about 100 MPa, about 68 MPa to about 100MPa, 25 MPa to about 95 MPa, about 40 MPa to about 95 MPa, about 50 MPato about 95 MPa, about 60 MPa to about 95 MPa, about 68 MPa to about 95MPa, 25 MPa to about 90 MPa, about 40 MPa to about 90 MPa, about 50 MPato about 90 MPa, about 60 MPa to about 90 MPa, or about 68 MPa to about90 MPa.

The gallium-substituted HA coatings may have an average thickness, asmeasured from the surface of the orthopedic implant to which it adheres,of about 150 nm or more, about 1 μm to about 50 μm, about 1 μm to about25 μm, about 1 μm to about 20 μm, about 1 μm to about 15 μm, about 1 μmto about 10 μm, about 1 μm to about 8 μm, about 3 μm to about 50 μm,about 3 μm to about 25 μm, about 3 μm to about 20 μm, about 3 μm toabout 15 μm, about 3 μm to about 10 μm, about 3 μm to about 8 μm, about5 μm to about 50 μm, about 5 μm to about 25 μm, about 5 μm to about 20μm, about 5 μm to about 15 μm, about 5 μm to about 10 μm, about 5 μm toabout 8 μm, or about 7 μm.

When applied to porous ingrowth surfaces like porocoat or gription, thegallium-substituted HA coatings may have a weight per unit surface areaof about 1 to about 100 mg/cm², about 1 to about 75 mg/cm², about 1 toabout 50 mg/cm², about 1 to about 25 mg/cm², about 1 to about 12 mg/cm²,about 5 to about 100 mg/cm², about 5 to about 75 mg/cm², about 5 toabout 50 mg/cm², about 5 to about 25 mg/cm² about 5 to about 12 mg/cm²,about 7 to about 15 mg/cm², about 7 to about 14 mg/cm² about 7 to about12 mg/cm², about 9 to about 15 mg/cm², about 9 to about 14 mg/cm², about9 to about 12 mg/cm², about 9 to about 11 mg/cm², about 9 to about 12mg/cm², or about 8 to about 12 mg/cm².

When an orthopedic implant coated with the gallium-substituted HAcoatings described herein is used in a patient or animal (e.g. canine),the in vivo resorption rates are such that the gallium-substituted HAcoating is resorbed within about 3 to about 15 weeks, about 4 to about15 weeks, about 5 to about 15 weeks, about 6 to about 15 weeks, about 3to about 14 weeks, about 4 to about 14 weeks, about 5 to about 14 weeks,about 6 to about 14 weeks, about 3 to about 12 weeks, about 4 to about12 weeks, about 5 to about 12 weeks, about 6 to about 12 weeks, about 1to about 6 weeks, or less than about 6 weeks.

In some embodiments, the gallium-substituted HA coating furthercomprises one or more additional therapeutic agents. The coating may bedoped with an additional material for improved osteoconduction and/ordelivery of anti-infective materials.

The therapeutic agent may include proteins, lipids,(lipo)polysaccharides, growth factors, cytostatic agents, hormones,antibiotics, anti-infective agents, anti-allergenic agents,anti-inflammatory agents, progestational agents, humoral agents,antipyretic agents, and nutritional agents. The therapeutic agent may bean osteoinductive substance, osteoconductive substance, or a substancethat is both osteoinductive and osteoconductive.

Metal Surface

The calcium phosphate layers described herein are disposed about asurface of an orthopedic implant. The surface may be a metal surface,such as a titanium or CoCr alloy surface or a titanium dioxide (TiO₂)surface. In some embodiments, the outer surface of the metal layer isamorphous and the rest of the metal layer is crystalline. In otherembodiments, the entire metal layer is crystalline. For example, theinterface between the surface and the calcium phosphate coating maycomprise an activated layer from which the calcium phosphate coatingnucleates and grows outward. It is to be understood that the entiresurface may be coated with HA or the surface may be masked such that apredetermined part of the surface is coated with HA.

The surface may be an activated metal surface. For example, when themetal surface is a titanium surface, the surface may be activated toform a titanate outer surface, which facilitates nucleation andincreased adhesion between the titanium surface and the calciumphosphate coating. Activation of the titanium surface also facilitatescontrolled crystal growth of the calcium phosphate layer therefromwithout further heat treatment, as will be further described below. Insome embodiments, the native oxide or oxide produced by passivationprocesses, is converted to titanate by hydroxide treatment. In someembodiments, the titanate is sodium titanate. Alternatively, crystallineTiO₂ may be applied to the implant core. Such crystalline films inducenucleation without further treatment. In some embodiments, the implantsurface is comprised of something other than titanium alloys. In thiscase, activation may be accomplished by deposition of nm scale films ofcrystalline TiOx on the implant surface. Alternatively, thin amorphousTiOx layers may be deposited and converted to titanate by hydroxidetreatment of the amorphous film. Additional means of activation includecreating surfaces that contain COOH, NH₂, or other charged moieties aswill be apparent to those skilled in the art.

In some embodiments, the entire core of the implant is titanium. Inother embodiments, titanium is coated on at least part of an implantcore, which, in turn, is coated with a calcium phosphate coatingdescribed herein. The implant core and/or surface may comprise amaterial such as CoCrMo or PEEK.

Alternatively, the implant may comprise a suitable material, such assilicon based materials, ceramic based materials, or polymer basedmaterials. Other contemplated materials include cobalt, chromium, iron,tantalum, niobium, zirconium, and alloys thereof (e.g., titanium alloysand tantalum alloys), as well as cobalt, cobalt-chromium alloys, andstainless steel. The implant may comprise biocompatible polymers,natural or synthetic polymers, such as polyethylene (e.g., ultrahighmolecular weight polyethylene or polyethylene oxide), polypropylene,polytetrafluoroethylene, polyglycolic acid, polylactic acid, otherpolysaccharides, and copolymers of any of the foregoing (e.g.,copolymers of polylactic acid and polyglycol acid) including tissueengineering scaffolds composed of synthetic polymers (e.g. poly HEMA)and biological macromolecules (e.g. collagen and chondroitin sulfate).

The metal or metal oxide layer may have a thickness of at least about 25nm, at least about 30 nm, at least about 35 nm, at least about 40 nm, atleast about 45 nm, at least about 50 nm, at least about 60 nm, at leastabout 70 nm, at least about 80 nm, at least about 90 nm, or at leastabout 100 nm. In some embodiments, the layer may have a thickness ofabout 25 nm to about 125 nm, about 30 nm to about 125 nm, about 35 nm toabout 125 nm, about 40 nm to about 125 nm, about 45 nm to about 125 nm,about 50 nm to about 125 nm, about 25 nm to about 100 nm, about 30 nm toabout 100 nm, about 35 nm to about 100 nm, about 40 nm to about 100 nm,about 45 nm to about 100 nm, or about 50 nm to about 100 nm. Films under100 nm may cease to display interference colors after hydroxideprocessing. The preferred thickness of the layer may be determined basedon the desired color profile of the orthopedic implant.

The crystal structure of the titanium surface can be characterized usingX-ray spectroscopy, such as X-ray powder diffraction. The titaniumsurfaces exhibit several characteristic 20 diffraction angles whencharacterized by X-ray powder diffraction. The X-ray spectra of titaniumfilms exhibit 2θ diffraction angles at about 26°, about 28°, about 32°,about 49°, and about 53°.

The metal surface may be modified prior to being coated with the HAcoating. For example, the metal surface may be modified with respect tosurface roughness in order to facilitate the adherence of the apatitecoating to the biocompatible substrate. Possible methods of modifyingthe roughness of the metal surface include acid etching or gritblasting.

Titanium Oxide Formation and Activation

As discussed above, a titanium oxide layer may be formed on anorthopedic prosthetic surface. Preferable processes for TiO₂ layerformation are conformal (non-line of sight) and produce films thatstrongly adhere to a core. Atomic layer deposition has been shown to becapable of producing both amorphous and crystalline films that are welladhered and of uniform thickness. Sol-gel processes andelectrodeposition of TiO₂ films also may be utilized.

After the surface is formed or otherwise available, surface activationmay be performed to encourage nucleation and growth of calciumphosphate. Basic conditions may be applied to the titanium oxide surfaceto activate it. In some embodiments, the titanium surface is treatedwith a hydroxide source, such as sodium hydroxide. Hydroxide treatmentproduces a porous titanate surface on the metal that facilitatesnucleation and growth of calcium phosphate.

Gallium Substituted Solution Deposited Hydroxyapatite (SoDHA-G) Process

The gallium-substituted hydroxyapatite coatings described herein areformed on the activated surfaces by deposition from supersaturatedsolutions. At sufficiently optimized supersaturation values, stablenuclei form and grow from active surfaces, resulting in the calciumphosphate coatings described herein. Without intending to be bound bytheory, it is believed that the growth predominantly occurs by aheterogeneous nucleation mechanism rather than a homogeneous mechanismunder the conditions further described below. The process results in agallium-substituted hydroxyapatite product, such as the coatingsdescribed above.

Calcium and phosphate/gallium solutions are prepared and adjusted todesired concentrations by dilution. The calcium and phosphate/galliumsolutions are mixed together, resulting in a solution that issupersaturated with respect to hydroxyapatite. Orthopedic implantprecursors, which have activated surfaces, are contacted with thesupersaturated solution, resulting in gallium-substituted hydroxyapatitecoating formation at a reproducible rate, under solution conditions thatdo not result in turbidity. In some embodiments, the substrate has acrystalline TiO₂ film surface, which is not necessarily activated. Insome embodiments, the substrate has an amorphous film surface that hasbeen treated with a base such as hydroxide. It is contemplated thatimplants may be masked to allow deposition only on selected portions ofthe implants.

Solution turbidity may be determined with the aid of optical sensorsthat evaluate the UV range. An Optek AS16F probe sensor operating at 430nm was utilized to detect turbidity due to homogenous nucleation insolution. Without intending to be bound by theory, coating at controlledrates is believed to have occurred primarily by heterogenous nucleation.

The degree of supersaturation in the coating solution depends on theactivities of calcium, phosphate, and gallium ions in solution, andsolution pH. Activities depend in turn on solution concentration,speciation, and ionic strength. The calcium and phosphate stocksolutions are mixed together, resulting in a solution that issupersaturated with respect to the desired calcium phosphate product.Orthopedic implants, which have activated surfaces, are contacted withthe supersaturated solution, resulting in gallium-substitutedhydroxyapatite coating formation at a rapid, reproducible rate.

Implants are coated in a solution that is supersaturated with respect toHA phases. In some embodiments, the supersaturated solution comprisesGa(NO₃)₃, Ca(NO₃), K₂HPO₄, KH₂PO₄, NaCl, andtris(hydroxymethyl)aminomethane (TRIS) buffer. The ratio of HPO₄²⁻/⁻H₂PO₄ may be selected to achieve the target solution pH. Othercounter-ions besides NO₃ and K may be utilized as those skilled in theart will appreciate. Calcium and phosphate/gallium concentrates may beobtained with a certified concentration and then diluted to workingconcentrations prior to blending to create the final supersaturatedsolutions.

The solutions used in forming HA include calcium cations at aconcentration of about 0.5 to about 1.5 mM, about 0.6 to about 1.5 mM,about 0.7 to about 1.5 mM, about 0.5 to about 1.3 mM, about 0.6 to about1.3 mM, about 0.7 to about 1.3 mM, about 0.5 to about 1.1 mM, about 0.6to about 1.1 mM, about 0.7 to about 1.1 mM, about 0.5 to about 1.05 mM,about 0.6 to about 1.05 mM, about 0.7 to about 1.05 mM, or about 0.62 toabout 1.05 mM. In some embodiments the calcium ion is Ca²⁺.

The solutions used in forming HA include phosphate anions at aconcentration of about 0.75 mM to about 1.75 mM, about 1.0 mM to about1.75 mM, about 1.25 mM to about 1.75 mM, about 0.75 mM to about 1.5 mM,about 1.0 mM to about 1.5 mM, about 1.25 mM to about 1.5 mM, about 0.75mM to about 1.35 mM, about 1.0 mM to about 1.35 mM, about 1.25 mM toabout 1.35 mM, about 0.75 mM to about 1.3 mM, about 1.0 mM to about 1.3mM, or about 1.25 mM to about 1.3 mM. In some embodiments the phosphateions are PO₄ ³⁻, HPO₄ ²⁻, H₂PO₄ ⁻, or a combination thereof.

The phosphate solutions used in forming HA include gallium cations at aconcentration of about 0.01 mM to about 0.4 mM, about 0.01 mM to about0.3 mM, about 0.01 mM to about 0.2 mM, about 0.01 mM to about 0.1 mM,about 0.01 mM to about 0.4 mM, about 0.05 mM to about 0.3 mM, about 0.05mM to about 0.2 mM, or about 0.05 mM to about 0.1 mM. In someembodiments the gallium ion is Ga³⁺. In some embodiments, the source ofgallium is Ga(NO₃)₃.

The solutions used in forming gallium-substituted HA have a pH of about7.5 to about 8, about 7.55 to about 8, about 7.6 to about 8, about 7.65to about 8, about 7.5 to about 7.9, about 7.55 to about 7.9, about 7.6to about 7.9, about 7.65 to about 7.9, 7.5 to about 7.85, about 7.55 toabout 7.85, about 7.6 to about 7.85, about 7.65 to about 7.85, 7.5 toabout 7.8, about 7.55 to about 7.8, about 7.6 to about 7.8, about 7.65to about 7.8, 7.5 to about 7.75, about 7.55 to about 7.75, about 7.6 toabout 7.75, about 7.65 to about 7.75, 7.5 to about 7.7, about 7.55 toabout 7.7, about 7.6 to about 7.7, about 7.65 to about 7.7, or about7.684. The pH may be the pH at the beginning of the coating process fora given coating iteration. The pH may be the pH when the solution is at25° C.

In some embodiments, a buffer is included in the supersaturated solutionto stabilize pH. In some embodiments, the buffer istris(hydroxymethyl)aminomethane (tris) buffer. The concentration of trisis from about 1 mM to about 10 mM, about 2 mM to about 10 mM, about 3 mMto about 10 mM, 1 mM to about 8 mM, about 2 mM to about 8 mM, about 3 mMto about 8 mM, 1 mM to about 6 mM, about 2 mM to about 6 mM, about 3 mMto about 6 mM, or about 5 mM.

A salt may be included in the supersaturated solution to increase ionicstrength. In some embodiments, the salt is sodium chloride. Theconcentration of salt is from about 100 mM to about 200 mM, about 100 mMto about 175 mM, about 100 mM to about 160 mM, 125 mM to about 200 mM,about 125 mM to about 175 mM, about 125 mM to about 160 mM, 140 mM toabout 200 mM, about 140 mM to about 175 mM, or about 140 mM to about 160mM.

The temperature of the solution during the coating process is from about40° C. to about 50° C., 42° C. to about 50° C., 44° C. to about 50° C.,46° C. to about 50° C., about 40° C. to about 48° C., 42° C. to about48° C., 44° C. to about 48° C., 46° C. to about 48° C., 46.5° C. toabout 47.5° C., or about 47° C. Implants may be maintained at a processtemperature within 0.5° C.

HA is a sparingly soluble salt with a K_(sp) on the order of 10⁻¹²⁰, andthus has a very narrow “meta-stable zone” from which controlledheterogeneous nucleation may occur. Surprisingly, a window was found toexist, allowing for relatively stable supersaturated solutions toprecipitate crystalline gallium-substituted HA onto an activated surfaceof an orthopedic implant in a controlled manner. In identifying thiswindow, it was observed that low supersaturated concentrations led toslow nucleation rates, while high supersaturated concentrations led touncontrolled, fast nucleation rates, accretion, and inconsistent growthon the substrate. Without intending to be bound by theory, coating underconditions of excessive supersaturation is believed to occur primarilyby homogenous nucleation and accretion.

Various conditions, may lead to increased solution stability. In someembodiments, solutions are mixed at room temperature rather than thetemperature at which the deposition process takes place. In someembodiments, calcium stock solutions are added to phosphate stocksolutions containing NaCl and tris. In some embodiments, the temperatureof stock solutions is not below room temperature. In some embodiments,the solution is housed in a vessel having smooth walls rather than roughwalls.

Surprisingly, it was possible to identify a window of supersaturatedsolution concentrations or, alternatively, a window of Gibbs freeenergy, that allowed for controlled gallium-substituted HA crystalgrowth in a desirable timeframe. The solutions used in thegallium-substituted SoDHA process were configured such that dG forformation of gallium-substituted HA was from about 7 kJ/mol to about 9kJ/mol, 7 kJ/mol to about 8.8 kJ/mol, 7 kJ/mol to about 8.6 kJ/mol, 7kJ/mol to about 9.4 kJ/mol, 7 kJ/mol to about 8.2 kJ/mol, 7.2 kJ/mol toabout 9 kJ/mol, 7.2 kJ/mol to about 8.8 kJ/mol, 7.2 kJ/mol to about 8.6kJ/mol, 7.2 kJ/mol to about 9.4 kJ/mol, 7.2 kJ/mol to about 8.2 kJ/mol,7.4 kJ/mol to about 9 kJ/mol, 7.4 kJ/mol to about 8.8 kJ/mol, 7.4 kJ/molto about 8.6 kJ/mol, 7.4 kJ/mol to about 9.4 kJ/mol, 7.4 kJ/mol to about8.2 kJ/mol, 7.6 kJ/mol to about 9 kJ/mol, 7.6 kJ/mol to about 8.8kJ/mol, 7.6 kJ/mol to about 8.6 kJ/mol, 7.6 kJ/mol to about 9.4 kJ/mol,7.6 kJ/mol to about 8.2 kJ/mol, 7.8 kJ/mol to about 9 kJ/mol, 7.8 kJ/molto about 8.8 kJ/mol, 7.8 kJ/mol to about 8.6 kJ/mol, 7.8 kJ/mol to about9.4 kJ/mol, 7.8 kJ/mol to about 8.2 kJ/mol, about 8.0 kJ/mol to about8.4 kJ/mol, about 8 kJ/mol, about 8.2 kJ/mol, or about 8.4 kJ/mol.

The dG for formation of HA without gallium and the relativesupersaturations of the solutions with respect to HA without gallium ofthe SoDHA HA process are listed Table 1. These representative values arenot limiting as to the possible values associated with the methodsdisclosed herein.

TABLE 1 Changes in Energy and Supersaturation Values for SoDHA Process(without gallium) dG HA dG OCP SS OCP SS HA −8.06451 −3.11966 3.23035320.72261 −8.11148 −3.14875 3.265878 21.09168 −8.14687 −3.16101 3.28095321.37415 −8.16934 −3.18283 3.307977 21.55537 −8.24149 −3.25443 3.39820822.14794 −8.27348 −3.25519 3.399187 22.41587 −8.34018 −3.32947 3.49542522.985 −8.34495 −3.33445 3.501971 23.0262 −8.34869 −3.33828 3.50701423.05862 −8.3538 −3.34325 3.513581 23.10291

As further described below, the gallium-substituted hydroxyapatitecoatings are formable from supersaturated solutions that remainsubstantially free of turbidity due to homogenous nucleation in solutionthroughout the coating process. Without intending to be bound by theory,deposition from solutions substantially free of turbidity due tohomogenous nucleation is believed to play a role in gallium-substitutedhydroxyapatite coatings deposited with predictable coating rates andhaving high crystallinity, uniform microstructure, and enhancedbiocompatibility.

Gallium-substituted HA is a sparingly soluble salt and has a very narrow“metastable zone” from which controlled heterogeneous nucleation andgrowth can occur. Surprisingly, it was possible to identify windows ofsupersaturation levels and temperatures that allowed for controlledgallium-substituted hydroxyapatite crystal heterogeneous nucleation andgrowth in a desirable timeframe. At these supersaturation values, stablenuclei form and grow from active surfaces, resulting in thegallium-substituted hydroxyapatite coatings described herein.

The gallium-substituted SoDHA process additionally comprises agitatingthe solution when it is in contact with the substrate. Too littleagitation during blending of stock solutions may destabilize thesolution. High shear agitation during blending of stock solutions maydestabilize the solution. Agitation may occur by stirring.

The process may include reducing the amount of air in contact with thesupersaturated solution. In some embodiments, the process may beperformed under inert atmospheric conditions, such as under an argon ornitrogen atmosphere. The inert atmosphere limits the dissolution ofcarbon dioxide into the supersaturated solution, which can change the pHwithout CaP precipitation, interfering with the use of pH as an internalprocess monitor. Under such conditions, the resultinggallium-substituted hydroxyapatite coatings are substantially free ofcarbonate.

The process occurs at a controlled, but relatively rapid coating rate.Coating rate can be described in terms of coating mass or coatingthickness. For a fixed number of implants in the coating solution,higher coating weights are obtained on implants with high specificsurface area like those coated with porous metal in-growth structures.Coating thickness however, is approximately independent of the specificsurface area of the implant. Finally, both mass and thickness basedcoating rates are a function of total surface area/coating solutionvolume as seen in FIG. 11.

The process deposits gallium-substituted HA such that thicknessincreases at a rate of about a rate of about 0.01 μm/h to about 10 μm/h,about 0.01 μm/h to about 5 μm/h, about 0.01 μm/h to about 4 μm/h, about0.01 μm/h to about 3 μm/h, about 0.01 μm/h to about 2 μm/h, about 0.01μm/h to about 1 μm/h, a rate of about 0.1 μm/h to about 10 μm/h, about0.1 μm/h to about 5 μm/h, about 0.1 μm/h to about 4 μm/h, about 0.1 μm/hto about 3 μm/h, about 0.1 μm/h to about 2 μm/h, about 0.1 μm/h to about1 μm/h, a rate of about 0.5 μm/h to about 10 μm/h, about 0.5 μm/h toabout 5 μm/h, about 0.5 μm/h to about 4 μm/h, about 0.5 μm/h to about 3μm/h, about 0.5 μm/h to about 2 μm/h, or about 0.5 μm/h to about 1 μm/h.

The process deposits HA on Gription at a rate of about 0.005 mg/hr·mm²to about 0.09 mg/hr·mm², about 0.005 mg/hr·mm² to about 0.025 mg/hr·mm²,0.005 mg/hr·mm² to about 0.0225 mg/hr·mm², 0.005 mg/hr·mm² to about 0.02mg/hr·mm², 0.005 mg/hr·mm² to about 0.0175 mg/hr·mm², about 0.005mg/hr·mm² to about 0.015 mg/hr·mm², about 0.0075 mg/hr·mm² to about 0.09mg/hr·mm², about 0.0075 mg/hr·mm² to about 0.025 mg/hr·mm², 0.0075mg/hr·mm² to about 0.0225 mg/hr·mm², 0.0075 mg/hr·mm² to about 0.02mg/hr·mm², 0.0075 mg/hr·mm² to about 0.0175 mg/hr·mm², about 0.0075mg/hr·mm² to about 0.015 mg/hr·mm², about 0.025 mg/hr·mm² to about 0.09mg/hr·mm², about 0.01 mg/hr·mm² to about 0.025 mg/hr·mm², 0.01 mg/hr·mm²to about 0.0225 mg/hr·mm², 0.01 mg/hr·mm² to about 0.02 mg/hr·mm², 0.01mg/hr·mm² to about 0.0175 mg/hr·mm², or about 0.01 mg/hr·mm² to about0.025 mg/hr·mm².

The coating process may be a “Constant Composition” or “VariableComposition” process.

In a constant composition process, reactants that are consumed bydeposition of gallium-substituted hydroxyapatite on implants aresemi-continuously added back to the deposition solution throughout thecoating process. The addition of reagents is performed based on the dropin pH that corresponds to precipitation of gallium-substitutedhydroxyapatite from solution. Thus, the amount of process reagents thatare added back to the deposition solution become a surrogate for theamount of gallium-substituted hydroxyapatite deposited on the implants.Without intending to be bound by theory, the equations that calculatethe composition of the “titrant” (the solutions that are added back tothe deposition vessel in response to a change in pH induced by CDHAprecipitation), when gallium is not included in the HA, may be:

TCaNO3=(Nb)(W_(CaNO3))+(10−x)Ceff

TP=(Nb)(W_(PO4))+6Ceff

TNaCl=(Nb)(W_(NaCl))−(20−2x)Ceff

TKOH=(Nb)(W_(KOH))+(14−2x)Ceff

where Ceff is equal to the moles of CaP precipitated per Liter of addedtitrant and x is the non-stoichiometric coefficient in CDHA, Nb=numberof burets adding titrants to solution, and W is the concentration ofreactants in the supersaturated solution.

In the variable composition process, chemical driving forces forprecipitation are allowed to fall from their initial conditions by anamount that maintains a high range of driving force rather than aconstant high driving force as is accomplished by the constantcomposition process. When the low limit of driving force is reached bydepletion of some fraction of coating reagents by precipitation of CaPfrom solution, the coating solution is discarded and a new coatingsolution is added to the deposition process vessel. One embodiment ofthe variable composition process utilizes the quantitative relationshipbetween change in solution pH and the amount and composition ofgallium-substituted hydroxyapatite that precipitates from the coatingsolution. This relationship can be used to determine when to discardcoating solutions and replace them with fresh solution as well as todetermine the predetermined process endpoint where gallium-substitutedhydroxyapatite coating weights have been met. The amount of buffer isselected to lessen the pH reduction that accompanies gallium-substitutedhydroxyapatite precipitation while allowing pH to reduce enough to allowthe use of pH change as an internal process diagnostic. In someembodiments, the pH measurements may be made intermittently rather thancontinuously. Coating rates are increased at lower deposition sequencetimes with greater numbers of coating sequences. In some embodiments,the coating solutions lack carbonate, which may assist with the use ofpH as a process monitor or control during coating formation.

Without intending to be bound by theory, the reactions, when gallium isnot included, are believed to proceed by the stoichiometry indicated byTable 2.

TABLE 2 Stoichiometry for HA and OCP Processes HA OCP Ca₁₀ (PO₄)₆ (OH)₂Ca₈ (HPO₄)₂ (PO₄)₄  −6 H₂PO₄  −2 HPO₄ −4 H₂PO₄ +12 H  +2 H +8 H +14H₂PO₄ −14 HPO₄  −8 HPO₄ +8 H₂PO₄ Totals  +8 H₂PO₄ −14 HPO₄ −10 HPO₄ +4H₂PO₄

As shown in Table 2, precipitation of calcium phosphate is accompaniedby a drop in calcium and phosphate concentrations, and a decrease in pH.These changes in concentration and pH result in a reduction in degree ofsupersaturation as the reaction progresses, along with a decrease indeposition rate.

The relationship between pH and amount of precipitate is scalable todifferent solution volumes. This relationship between change in pH andamount of phase precipitated may be utilized as a process monitor toensure that a predictable amount of precipitate is formed.

The pH of the supersaturated solution may be monitored to determine theextent of coating that has taken place. In some embodiments, thesubstrate is contacted by the solution until one or more of the calciumconcentration, phosphate concentration, and pH decrease to apredetermined level.

Although nucleation rates, growth rates, and relative driving forces forgallium-substituted SoDHA change as gallium-substituted HA precipitates,a process was developed to minimize changes in these values asprecipitation proceeds. The process used for coating the implants was avariable composition process. As used herein, a variable compositionprocess refers to a process that allows for change in thermodynamicvariables over the course of the process. In the variable compositionprocess described herein, implants may be coated by multiple batches ofsolution, allowing ion concentrations and pH to fall only to apredetermined level during each of the iterations. To reduce the extentof concentration changes, multiple sequential depositions were used,with each deposition sequence comprising contacting the orthopedicimplant with fresh solution. The pH change associated with depositionmay be reduced by buffering the solution with a buffer, such as TRISbuffer.

In some embodiments, three sequential depositions were performed. For athree sequential deposition process, concentration changes during eachdeposition sequence are reduced by two thirds compared to one depositionsequence. In some embodiments, only one deposition sequence isperformed. In some embodiments, 2 or 3 deposition sequences areperformed. 1 to 10, 2 to 10, 3 to 10, 1 to 5, 2 to 5, or 3 to 5deposition sequences may be performed. In some embodiments, the numberof deposition sequences employed depends on the ratio of the surfacearea of the implant to the volume in the coating vessel. Larger implantsurface area/volume ratios may correspond with a larger number ofshorter coating sequences. Lower surface area/volume ratios maycorrespond with fewer sequences of longer duration per sequence. Thecombination of pH buffering and refreshing of solutions minimizes thechange in thermodynamic driving forces and may help to ensure that thesame calcium phosphate phase is produced throughout the depositionprocess.

The total contact time with the solution deposition composition inaccordance with the inventive method typically is about 30 minutes ormore. The total contact time preferably is about 8 hours or less. Morepreferably, the biocompatible substrate is subjected to multiplesequence contact times of about 1 minute to about 2 hours, about 1minute to about 1 hour, about 1 minute to about 30 minutes, about 5minutes to about 2 hours, about 5 minutes to about 1 hour, about 5minutes to about 30 minutes, about 2 hours or less, about 1 hour orless, or about 30 minutes or less. In general, longer total contacttimes and shorter coating sequences provide greater thicknesses of thebioactive hydroxyapatite coating. Additionally, the contact time isdependent on the number of bioactive substrates being coated at any onetime.

In some embodiments, the relationship between weight of precipitate andchange in pH is used to monitor the progression of the SoDHA-G process.In additional embodiments, the relationship between weight ofprecipitate and change in calcium and/or phosphate concentration may beused to monitor the progression of the SoDHA-G process. In otherembodiments, the process is performed for a predetermined amount of timeand pH, calcium concentration, and phosphate concentration are notmonitored.

In some embodiments, a supercritical fluid may be employed to drySoDHA-G coatings. This process includes displacing water from a coatingwith an organic solvent followed by supercritical fluid extraction.After SoDHA-G coating formation, organic solvent exchange is performedby immersing coated articles in the organic solvent for a predeterminedperiod of time. After displacement of the organic solvent in thecoating, the coated article is placed in a vessel where a supercriticalfluid is introduced. Next, the vessel is depressurized to atmospherewhile maintaining the temperature above the critical temperature of thesupercritical fluid. In this way the supercritical fluid isdepressurized directly from a supercritical state to a gas, which avoidscreation of liquid capillary forces that may cause cracks.

In some embodiments, the organic solvent is an alcohol. For example, theorganic solvent may be methanol, ethanol, or isopropanol. In someembodiments, the supercritical fluid is supercritical CO₂ (scCO₂).

Additionally, in some embodiments, the SoDHA-G coatings may be exposedto hydrothermal re-precipitating conditions. After SoDHA-G coatingformation, the coatings may be placed in phosphate-gallium solution andheated. This hydrothermal treatment may be performed at temperaturesfrom about 50° C. to about 350° C., about 60° C. to about 350° C., about70° C. to about 350° C., about 80° C. to about 350° C., about 50° C. toabout 150° C., about 60° C. to about 150° C., about 70° C. to about 150°C., about 80° C. to about 150° C., about 50° C. to about 99° C., about60° C. to about 99° C., about 70° C. to about 99° C., about 80° C. toabout 99° C., about 50° C. to about 95° C., about 60° C. to about 95°C., about 70° C. to about 95° C., about 80° C. to about 95° C., about50° C. to about 90° C., about 60° C. to about 90° C., about 70° C. toabout 90° C., about 80° C. to about 90° C., about 50° C. to about 85°C., about 60° C. to about 85° C., about 70° C. to about 85° C., about80° C. to about 85° C., about 50° C. to about 80° C., about 60° C. toabout 80° C., or about 70° C. to about 80° C. The coatings may be heatedfor times from about 15 minutes to about 24 hours, about 15 minutes toabout 4 hours, about 15 minutes to about 3 hours, about 15 minutes toabout 2 hours, about 30 minutes to about 24 hours, about 30 minutes toabout 4 hours, about 30 minutes to about 3 hours, about 30 minutes toabout 2 hours, about 1 hour to about 24 hours, about 1 hour to about 4hours, about 1 hour to about 3 hours, about 1 hour to about 2 hours, orabout 2 hours.

The methods described herein maximize the amount of material that growson the substrate, and minimize the amount that accretes onto the surfacefrom material homogeneously precipitated in suspension. Additionally,these methods provide for a controlled, predictable deposition rate,produce films with high adhesion and cohesion, and produce a uniformmicrostructure that degrades uniformly without release of particulates.Predictable deposition rates allow targeted film thicknesses to bereadily achieved. The methods also provide suitable coverage of porousstructures and are suitable for various implant geometries.

Definitions

As used herein, relative supersaturation of a product (S) is defined bythe following equation: S=[IAP/K_(sp)]^(1/v), where IAP is the ionicactivity of the product, K_(sp) is the solubility constant of theproduct, and v is the number of ions in the unit formula of the product.

As used herein, Gibbs free energy change (dG) associated with a phasechange is defined by the following equation: dG=RT/v*ln[IAP/K_(sp)],where R is the universal gas constant, T is absolute temperature, IAP isthe ionic activity of the product, K_(sp) is the solubility constant ofthe product, and v is the number of ions in the unit formula of theproduct.

As used herein, relative supersaturation S, is equal to (IAP/Ksp)^(1/v).

As used herein, homogenous precipitation or homogenous nucleation refersto nucleation of a solid phase from a supersaturated solution that doesnot involve a foreign surface, resulting in a turbid supersaturatedcoating solution.

As used herein, heterogeneous precipitation or heterogeneous nucleationrefers to nucleation of a solid phase on an impurity phase from asupersaturated solution that is substantially free of turbidity duringthe deposition process.

As used herein, “octacalcium phosphate” or “OCP” refers to a calciumphosphate having the formula Ca₈(HPO₄)₂(PO₄)₄.

As used herein, supersaturated refers to a solution in which a solute isconcentrated beyond equilibrium. When concentration is above thesaturation point, the solution is said to be supersaturated.

As used herein, in vitro, in reference to dissolution studies, means ina tris buffered saline solution at pH 7.4, as described in ASTM F1926.

Example 1—Activation of CoCr by Atomic Layer Deposition of TiO₂ Films

TiO₂ films were prepared on CoCr grit blast surfaces by Beneq (Helsinki,Finland) by atomic layer deposition. The films were produced from TiCl₄and H₂O precursors. Amorphous films were produced at 90° C. andcrystalline (Anatase plus Rutile) films were produced at 200° C. Filmswere activated with hydroxide, according to the methods described inExample 3 (4 hrs, 5M NaOH, 60° C.). 500, 200, 100, and 50 nm amorphousfilms (500A, 200A, 100A, and 50A) and 500 and 200 nm crystalline films(500° C., 200° C.) were evaluated for their ability to formhydroxyapatite coatings according to the SoDHA method using nominalconcentrations, as further described in Examples 5 and 6.

HA coating weight for the samples ranged from about 6 mg to about 8 mg,as shown in FIG. 1. Both amorphous and crystalline films were able tonucleate HA after activation by strong base. Coating experiments showedthat deposition occurred for as deposited crystalline titanium oxide,but at lower rates than observed for NaOH etched amorphous orcrystalline titanium oxide.

A scanning electron microscopy (SEM) image of the 200 nm-thick,activated amorphous film, prior to HA coating is shown in FIG. 2. An SEMimage of the 200 nm-thick, activated crystalline film, prior to HAcoating is shown in FIG. 3. The characteristic titanate topography wasapparent on amorphous films. Films prepared over 100 nm thick showedinterference colors after hydroxide treatment.

Grazing angle X-ray diffraction (XRD) spectra were obtained foramorphous and crystalline titanium coatings at 200 nm-thick and 500nm-thick before and after activation with NaOH. The XRD spectra for theamorphous films are shown in FIG. 4. The XRD spectra for the crystallinefilms are shown in FIG. 5.

Example 2—Electrolytic Formation of TiO₂ Films on CoCr Alloy

An electrolyte solution of 0.05 M TiCl₄ and 0.25 M H₂O₂ in a mixedmethanol/water (3/1 vol %) solvent was prepared. The pH of the solutionwas fixed between 0.9 and 1.0. All chemicals were ACS grade. To preparethe electrolyte solution, TiCl₄ was slowly added to the solvent,followed by H₂O₂. During the addition of H₂O₂, an immediate color changefrom transparent to dark orange was observed, indicating the formationof a peroxo-complex. Electrolytes were stored at about 4° C. afterpreparation and pH measurement and, if necessary, pH adjustment.Electrodeposition was performed galvanostatically up to the desiredcharge density. The temperature was fixed by a cryostat to 0° C. Ahomemade Labview program (controlling a Xantrex XDC 300-20 power source)was built to control current charge density while recording voltage-timecurves. The applied charge density was fixed in the range form 2.5 C/cm²to 40 C C/cm². The current density was varied between −50 mA/cm² to −50mA/cm².

Good film uniformity was obtained in 0.05 M TiCl₄, 0.5 M H₂O₂ in a mixedmethanol/water (3:1 vol. %) solvent (pH=0.97). Good growth occurred at−1.1 V for 1 hour at 60° C. FIG. 6 is an SEM image showing a titaniumcoating electrodeposited under these conditions on a CoCrMo substrate.

Example 3: Titanium Surface Activation

1 inch diameter Ti6-4 disks coated with DePuy Gription porous metalcoating were cleaned and activated by the following steps. Disks wereset in a container with reverse osmosis (RO) water and alkalinedetergent for 15 min with a sonicator 2 times. Next, disks were set in acontainer with only RO water for 15 minutes with a sonicator 2 times. 4disks were placed in a 500 mL beaker and 200 mL of 5M NaOH was added.The disks were placed in secondary containment and a loose cap was setover the top of the beaker. The temperature of the beaker was set to 60°C. and held for 4 hrs. The desks were removed from the beaker and rinsedin RO water in a sonicator for 15 minutes 4 times. Disks were left in a60° C. oven overnight to dry. No effect of heat treatment of thisactivation layer on the tendency to promote nucleation and growth of CaPcoatings was found in the methods disclosed herein, and examplesreported below were performed without heat treatment of the activatedsurface. Coating experiments showed that deposition occurred forcrystalline titanium, but at lower rates than observed for NaOH etchedamorphous titanium.

Example 4: Stock Solution Preparation

Concentrate and stock solutions for HA coating of 1 inch diameter disksin a 1 L vessel were prepared by the following steps.

A 36 mM Ca solution was prepared. A clean 2-liter bottle was obtainedand a magnetic stir bar was placed in the bottle. 8.50194 g of Ca(NO₃)was weighed out and poured into the 2-liter bottle. The bottle waspurged with Argon for 3-5 minutes. 1000 mls of deionized (DI) water witha resistivity of 18 MΩ or higher was added to the bottle. The bottle wasplaced on stir plate and its contents were stirred until Ca(NO₃) wasfully dissolved. The solution was filtered using a 0.22 μm cell culturevacuum filter (Corning, Funnel Volume, 1000 mL; Receiver: 90 mm; PoreSize: 0.22 um; PES, No.:431098).

A 40 mM phosphate (P_(i)) solution was prepared. A clean 2-liter bottlewas obtained and a magnetic stir bar was placed in the bottle. 5.444 gof KH₂PO₄ was weighed out and poured into the 2-liter bottle. 19.0387 gof Tris and 273.675 g NaCl were weighed out and added to the bottle. Thebottle was purged with Argon for 3-5 minutes. 898.1 mL of 18 MΩ orhigher DI water was added. Using a manual pipette, 5.8 mL of 6N HCl wasadded to the bottle. The bottle was placed on a stir plate and stirreduntil the Tris, NaCl, and KH₂PO₄ were fully dissolved. The final volumeof the solution was 1 L and the pH of the solution was approximately8.23 at 25° C. If necessary, pH may be adjusted to this value using HClor NaOH. The solution was filtered using a 0.22 um cell culture vacuumfilter (Corning, Funnel Volume, 1000 mL; Receiver: 90 mm; Pore Size:0.22 um; PES, No.:431098).

495.3 mls of a 2.0787 mM Ca stock solution was prepared. The previouslyprepared 36 mM calcium solution was placed on a stir plate and stirredfor five minutes. A clean 1-liter bottle was purged with Argon. 28.6 mLof 36 mM calcium solution was added using a pipette. 466.7 mL of 18 MΩor higher DI water was added.

500 mL of 2.5690 mM P₁ stock solution was prepared. The previouslyprepared 40 mM phosphate solution was placed on stir plate for fiveminutes. A clean 1-liter bottle was purged with Argon. 32.112 mL of 40mM phosphate solution was added using a pipette. 467.888 mL of 18 MΩ orhigher DI water was added.

A 1.7792 mM Ca solution was prepared. The previously prepared 36 mMcalcium solution was placed on a stir plate and stirred for fiveminutes. A clean 1-liter bottle was purged with Argon. 36 mM calciumsolution and 18 MΩ DI water were mixed to achieve the desiredconcentration.

A 2.2262 mM 500 mL P₁ solution was prepared. The previously prepared 40mM phosphate solution was placed on stir plate for five minutes. A clean1-liter bottle was purged with Argon. 40 mM phosphate solution and 18 MΩDI water were mixed to achieve the desired concentration.

A gallium/phosphate stock solution was prepared. First, approximately 2L of 1.2730 mM Phosphate stock solution was prepared by dilution of 40mM phosphate concentrate, as described above. This solution was setaside and a second, clean 2 L bottle was obtained. GaNO₃ hydrate wasweighed on a balance, based on the desired wt % Ga in theGaNO₃/Phosphate solution, and added to a second empty, clean 2 L bottle.Approximately 200-300 mL of phosphate stock was added to the 2 L bottlecontaining the GaNO₃. A cap was placed on the bottle containing theGaNO₃ and 200-300 mL of phosphate stock. A cloudy solution was formed byshaking the bottle. The solution was transferred into a clean, 500 mLvolumetric flask. Phosphate stock was added to the volumetric flaskuntil the fill line was reached. The contents of the volumetric flaskwere transferred back into the 2 L bottle that previously contained thesolution. The volumetric flask was filled two more times with phosphatestock and each time the stock was added to the 2 L bottle with GaNO₃.Another 50 mL of phosphate stock was measured out in a graduatedcylinder and added to the GaNO₃ solution. The 2 L bottle containing thesolution was capped and shaken again to double-check that all solidshave been dissolved to form the GaNO₃/Phosphate solution.

The gallium/phosphate prepared at ratios of 5 to 20 wt % Ga. Afterthorough mixing the pH was adjusted between 8.3 and 8.4 with micro-literadditions of 6N NaOH.

Example 5: HA Coating by Solution Deposition in 1 L Vessel

1 inch diameter porous metal coated titanium coupons were coated. Acover for a 1 L jacketed vessel was provided to allow for an Ar covergas during process the deposition process. 500 mLs of 2.569 mM phosphatestock solution prepared according to Example 4 was added into the 1 Ljacketed vessel, and the vessel was placed on a stir bar plate. The stirbar was turned on at 200 rpm. Next, 495.3 mL of 2.0787 mM Ca stocksolution, prepared according to Example 4 was poured into the vessel.Total volume at 25° C. was 1 L due to volume expansion associated withNaCl dilution. The pH of the solution was 7.68 and the calculated dG was8.242. Relative SS for HA was 22.15 at the initiation of the coatingprocess. A heated water bath was circulated through the jacketed vessel,and the solution was allowed to reach 47° C. The temperature wascontrolled within 0.5° C. Temperature sensors were calibrated to a NISTtraceable RTD. The etched (activated) disks were placed in fixtures thatallowed disks to be suspended in the 1 L jacketed vessel.

After coating, the disks were moved into a first container of DI waterand allowed to soak for 1 minute. Next, the disks were moved from thefirst container to a second container of DI water and allowed to soakfor 1 minute. Then, disks were moved from the second container to athird container of DI water and allowed to soak for 1 minute. Aftersoaking, the disks were moved to a 6-well tray and placed in a 60° C.oven to dry for 60 min.

This process was repeated three times with a fresh solution each time.Each sequence was controlled to a fixed value of dpH. For larger implantSA/V ratios a larger number of shorter coating sequences may be used.For lower SA/V ratios, fewer sequences of longer duration per sequencemay be used. At the SA/V ratio equal to 941 mm²/L used in the animalstudy (Example 17), a total coating time of 5.73 hours with 2.35 coatingsequences of 2.44 hour duration per sequence was used.

After coating, the disks were moved into a first container of DI waterand allowed to soak for 1 minute. Next, the disks were moved from thefirst container to second container of DI water and allowed to soak for1 minute. Then, disks were moved from the second container to a thirdcontainer of DI water and allowed to soak for 1 minute. After soaking,the disks were moved to a 6-well tray and placed in a 60° C. oven to dryfor 60 min.

Example 6: Full Scale Process Validation

The nominal process described in Example 5 was repeated using a “fullscale” system shown in FIG. 7. The full scale system is designed to coatup to 40 acetabular cups or 16 hip stems in a single coating run of oneor more coating sequences. A series of coating runs were made utilizingboth standard DePuy TriLock BPS hip stems or hip stems modified toaccept one-inch diameter coupons (shown in FIG. 17) were made at nominalas well as + and—process limits. Process limits were defined as + and−2% of Ca and Phosphate concentrations and +−0.06 pH units. Coatingswere characterized by various methods as described in the examples.

Example 7: Use of dpH as a Process Monitor

pH and precipitate mass were monitored for the SoDHA process describedin Example 5 at nominal values, the SoDHA process described in Example 5at nominal values without tris, and the SoDHA process described inExample 5 at nominal values with 5 mM. The relationship between pH andamount of precipitate is scalable to different solution volumes andbuffer strengths using a solution thermodynamics software such as“Chemist” version 1.0.3 from Micromath Scientific Software, 9202Litzsinger Road Saint Louis, Mo. 63144. This relationship between changein pH and amount of phase precipitated may be utilized as a processmonitor to verify that a targeted amount of precipitate is formed. Aspreadsheet calculator was constructed based on the relationshipssummarized in Table 2 to calculate the concentrations and activities ofreactants as a function of amount of CaP phase precipitated. CaP phasesthat can be modeled by this calculator include stoichiometric HA,stoichiometric OCP, non-stoichiometric CDHA, and mixtures of HA or CDHAwith OCP. For each increment of CaP phase precipitated, the reducedreactant concentrations were input into Chemist, which calculates thesystem pH based on buffer type and levels being analyzed. FIG. 10 showspredicted vs experimental plots of pH as a function of total mgprecipitated of CaP comprised of:

1) CDHA of formula Ca_(10-x)(PO₄)_(6-x)(HPO₄)_(x)(OH)_(2-x) with x=to1.0

a) without TRIS buffer

b) with 5 mM TRIS buffer

2) A mixture of 80% OCP and 20% CDHA with x=1.5 with 5 mM TRIS.

Experimental values in this plot are taken from Example 5.

Example 8: Characterization of HA Coating

FIG. 8 shows a scanning electron microscope (SEM) image of SoDHA HAcoated flat titanium disc at 15000× magnification. FIGS. 9A and 9B showscanning electron microscope (SEM) images of a SoDHA HA coated porousingrowth structure (Gription) at 100× and 400× magnification,respectively. It is seen the HA coating was continuous over the discsurface.

FIG. 11 shows the effect of substrates having various surface area (mm²)on deposition rate (mg/hr) at fixed dG, temperature, and degree ofagitation. Materials were coated with HA at nominal values in the fullscale deposition system, using nominal conditions as described inExample 5. It can be seen that coating rate decreased as surface areaincreased. This trend may be utilized to estimate coating time based onsurface area for a given substrate.

The density of bulk HA and OCP are similar at about 3.1 g/cm³. Depositsof HA prepared at nominal values according to Example 5 weighed 7 mgs onflat coupons, had a surface area of 5.07 cm², and had a thickness ofabout 7 microns, corresponding to an actual density of about 1.97 g/cm³and a porosity of about 36%.

Example 9: Full Scale Process Characterization

The coating prepared according to the full scale system process ofExample 5 at nominal and process limit values met the followingspecifications:

Coating weight: 0.08 to 0.12 mg/mm² of projected surface area

% crystalline HA by Rietveld analysis: >70%

% of amorphous calcium phosphate: <detection limit by DSC, as describedin Example 11.

XRD crystallite size parameters:

1/β (200) 1.63+−0.13

1/β (002) 4.15+−0.10

1/β (210) 1.5+−0.10

Tensile adhesion as determined according to ASTM F1147 (measured on gritblasted flat): >68 MPa Ca/P ratio: 1.39 to 1.65

FIGS. 12-16 summarize data obtained from the full scale system evaluatedat nominal and process limit conditions. In all cases, the error barsare equal to 3 standard deviations of the data.

FIG. 12 shows the Ca/P ratio for HA coated materials prepared bydeposition in the full scale system according to Example 6 at nominaland process limits. Ca/P ratio was determined by wet chemical methods.“NIST” refers to National Institute of Standards and Technology standardhydroxyapatite.

FIG. 13 shows the crystallinity of the coatings as determined by XRD forHA coated materials prepared by deposition in the full scale systemaccording to Example 6 at nominal and process limits. Crystallinity wasdetermined based on areas under selected diffraction peaks on thecoating and compared to the same peak areas on the highly crystallineNIST standard. The balance of material not reported is not amorphous asfound in PSHA deposits. Crystallinity values less than 100% reflect thefine grain size of the films and the fact that grain boundaries aredisordered and do not contribute much to diffracted peak areas.Amorphous content is determined by DSC.

FIG. 14 shows the percentage of HA as crystalline material out of allcrystalline material in the HA coated substrates prepared by depositionin the full scale system according to Example 6. In other words, it is ameasure of the phase purity of the films.

FIG. 15 shows tensile adhesion as determined by ASTM F1147 of HA filmsprepared by deposition in the full scale system according to Example 6.

FIG. 16 shows shear adhesion as determined by ASTM F1044 of HA filmsprepared by deposition in the full scale system according to Example 6.

Example 10—Differential Scanning Calorimetry (DSC)

Differential Scanning calorimetry (DSC) has been previously investigatedto directly observe, and qualitatively measure, the thermalrecrystallization of amorphous calcium phosphate phases in plasmasprayed hydroxyapatite materials. It has been reported that amorphouscalcium phosphate recrystallizes by a series of exothermic reactionsthat occur at different temperatures (within the range of 500° C. and750° C.) and with different amplitudes dependent upon changes in theplasma spraying parameters (e.g. plasma power, feed rate, coatingthickness etc.). Reactions are seen by the exothermic peak atapproximately 500-550° C. (the crystallization of hydroxyl-richamorphous regions in the material), the exothermic peak at approximately600-650° C. (the diffusion of hydroxyl ions into hydroxyl-depletedregions), and the exothermic peak approximately 720-750° C.(crystallization of oxyapatite phase).

In this example, DSC was used to observe any phase transitions (e.g.recrystallization) that can occur in hydroxyapatite/calcium phosphatematerials as a consequence of impurities and/or amorphous phases onheating up to 725° C.

Solution deposited SoDHA HA powders prepared according to Example 5 werescraped from flat Ti64 witness coupons. Each powder material was testeda minimum of 3 times using the DSC. The Pyris DSC analysis software wasused to measure the peak areas and peak positions (between 550 and 710°C.) for all powder samples, and the resulting recrystallization energies(J/g) were calculated.

DSC analysis of SoDHA powders scraped from coated Ti witness coupons isshown in FIG. 24, which shows no discernible exothermic peaks onheating.

In the area of interest, i.e. 550° C. and 710° C., there were noexothermic peaks seen in the DSC heating curves generated for scrapedSoDHA powders, indicating very little, if any, glassy amorphous phases.Based on the DSC curves, there was less than 2 wt % glassy amorphousmaterial in the SoDHA powders tested. It was also observed that theSoDHA powders analyzed using DSC were a gray color coming out of thetest, indicating a small amount of titanium is removed from thesubstrates on scraping and subsequently oxidizes during DSC testing.

Example 11: First Gallium-Substituted SoDHA Coating Trial

Gallium doping studies began by adding gallium ions to the calcium stocksolution. The process described in Example 6 was repeated, except thegallium/calcium solution was used instead of the calcium solution. Thismethod destabilized the deposition process, and gallium found in filmsformed in this manner was present as a separate phase. Turbidity wasobserved at various time intervals following gallium nitrate addition tothe calcium stock solution. This was reflected in low coatingefficiency, and gallium detected in coatings produced in this manner waspresent as discrete gallium bearing particles. There was a considerableamount of loosely bound calcium phosphate precipitate on the surface ofthe desired SoDHA coating.

Example 12: Gallium-Substituted SoDHA Coating

The process described in Example 6 was repeated, except as follows. Thegallium/phosphate solution was used instead of the phosphate solution.500 mL of the calcium solution was added to the gallium/phosphatesolution. The pH at the start of these experiments was typically between7.68-7.8.

Surprisingly, gallium was incorporated into the HA lattice by addinggallium to the stock solution containing phosphate and TRIS and NaCl.This incorporation is demonstrated by data showing a gallium dosedependent shift in lattice parameter, crystallite size, and BET surfacearea, as further described in Example 9. Gallium-substituted SoDHAcoating trials indicate that addition of Ga-salt (Ga(NO₃)₃) in Trisbuffered phosphate(Pi)-stock was produced with coating efficienciesamenable to heterogeneously coating a test article without solutionturbidity.

The process was repeated using a “full scale” system in the coatingvessel shown in FIG. 7. In the full scale system, 40 acetabular cupswere placed in 64 L of the supersaturated solution.

Example 13: Ga-Substituted HA Coating XRD Characterization

In this example, the gallium-substituted HA coatings prepared bydeposition in the full scale system according to Example 12 werecharacterized by XRD.

Six coated discs, representative of 0 wt %, 5 wt %, 10 wt %, 15 wt % and20 wt % Ga in HA lattice added to the coating solution, were analyzed byX-ray diffraction (XRD) spectroscopy.

Scraped gallium-substituted HA powders were analyzed by powder XRD (andthe associated Rietveld and FWHM analyses). Care was taken to scrape thecoated HA material down to the Ti substrate without generating Ticontamination in the powder. Due to the relatively low mass (4-9 mg) ofpowder on each of the coated flat substrates, 6 substrates were scrapedto obtain 15-20 mg of gallium-substituted HA powder. XRD scans for theas coated gallium-substituted HA discs were measured with the backgroundcalculated and removed using Panalytical X'Pert software.

An overlay of the XRD plots is shown in FIG. 18, which indicates thatthe gallium-substituted HA coatings were phase pure, within thedetection limits of the X-ray equipment (no XRD peaks associated withsecond phases were observed), and the HA coating was highly textured inthe 001 crystal orientation.

For the sample with 20 wt % gallium, Table 3 shows 20 values, togetherwith the relative intensities of various peaks, as determined using XRDof the gallium-substituted HA samples. Background was calculated andremoved using Panalytical X'Pert software. The relative intensity ofeach the peak was calculated as a percentage of the most intense peak inthe scan. It is noted that not all peaks published in the NIST SRM datafor HA were observed in the as coated gallium-substituted HA coating dueto preferred orientation in the coating. It also is noted that the 100%intensity peak in a randomly oriented HA powder is the (211) peak,occurring at 31.70° 2θ, whereas the 100% intensity peak observed for ascoated gallium-substituted HA discs is the (002) peak occurring at about25.95° 2θ. The increased intensity of the (002) peak indicates highlyoriented crystals in the 001 direction.

TABLE 3 XRD peak spacing and intensity for 20 wt % gallium-substitutedHA Relative intensity d-spacing 2θ (%) 002 25.95 ± 0.02 100 211 31.70 ±0.02 45-46 112 32.21 ± 0.02 47-48 202 34.09 ± 0.02 21-22 213 49.61 ±0.02 14.5-15.5 004 53.37 ± 0.02 18-19

As shown in FIG. 18, as the wt % Ga was increased, a reduction in the HAcrystalline phase content was observed. This is noted from reduced peakintensities in the XRD traces as wt % Ga is increased. It is also notedthat a systematic shift in the (002) peak was seen to higher 2θ angles(corresponding to decreases in d-spacing) as the Ga was increased in thegallium-substituted SoDHA coatings. Table 4 shows the average HA (002)peak positions measured from the coated discs formed from solutions withvarying concentrations of gallium. The progressive decrease in latticed-spacing is consistent with smaller Ga³⁺ ions (0.62 Å) substitutinginto the Ca1 lattice site in the HA lattice for larger Ca²⁺ ions (0.99Å).

TABLE 4 Average and standard deviation of gallium-substituted HA (002)XRD peak spacing at varying gallium concentrations wt % Ga in (002)d-spacing (Å) Solution Ave Std. Dev.  0% 3.4506 0.0006  5% 3.4491 0.001610% 3.4456 0.0013 15% 3.4400 0.0016 20% 3.4348 0.0011

The analysis of the (002) peak shifts confirms the observations from ascoated discs, that (002) d-spacing decreases as wt % Ga is increased inthe SoDHA coating. This is consistent with increasing Ga substitution ofCa1 sites in the HA lattice. These data reveal that gallium wassuccessfully substituted into the lattice of hydroxyapatite.

Example 14—Additional Gallium-Substituted HA Coating Results

The wt % of gallium in the SoDHA lattice was determined forgallium-substituted HA coatings formed according to Example 12 fromsolutions having 5 wt %, 10 wt %, and 20 wt % gallium nitrate, as shownin FIG. 20.

Results presented in Table 5 show the amounts of crystallinehydroxyapatite, amorphous and disordered crystalline content ingallium-substituted hydroxyapatite samples formed from solutions withvarying amounts of Ga according to Example 12.

TABLE 5 Average wt % crystalline and amorphous content in gallium-substituted HA at varying gallium concentrations Average wt. % wt % Gain Average wt. % Amorphous/Disordered Solution Crystalline HACrystalline  0% Ga 91.7 8.2  5% Ga 74.5 25.4 10% Ga 64.8 33.0 15% Ga53.1 46.9 20% Ga 38.7 61.2

As shown in Table 6, it is seen from FWHM analyses that the averagecrystallite size in the (200), (002) and (210) directions are reducedconsiderably as Ga is introduced into the HA lattice. Averagecrystallite size in the (200), (002) and (210) directions is shown inTable 7. It is noted that the crystallite size in the (200) directionbecomes too small to measure after just 10 wt % Ga addition. Withoutintending to be bound by theory, it is proposed that crystallite sizereduction in the HA coating is the primary reason for the calculateddecrease in crystallinity from the Reitveld analyses due to the peakbroadening associated with the very small crystal sizes.

TABLE 6 Average 1/β of gallium-substituted HA XRD peaks at varyinggallium concentrations 1/β HA 1/β HA 1/β HA wt % Ga in Solution (200)(002) (210)  0% Ga 2.51 6.50 1.67  5% Ga 2.10 3.34 1.52 10% Ga 1.38 2.321.23 15% Ga — 1.82 0.92 20% Ga — 1.49 0.64

TABLE 7 Average crystallite size (τ) of gallium-substituted HA XRD peaksat varying gallium concentrations τ HA τ HA τ HA wt % Ga in Solution(200) (nm) (002) (nm) (210) (nm) NIST SRM 2910a 38.72 82.07 119.58(Measured) NIST SRM 2910a 36.26 81.76 130.09 (Reported) Nominal 20.5068.61 49.19  5% Ga 17.11 35.27 44.85 10% Ga 11.28 24.45 36.15 15% Ga NotMeasurable 19.16 27.14 20% Ga Not Measurable 15.75 18.89

Example 15—FTIR Characterization

An FTIR spectrum was obtained of the gallium-substituted SoDHA HA formedin Example 12. The FTIR spectrum is shown in FIG. 21.

Example 16—Dissolution

Dissolution rates of the gallium-substituted SoDHA coating formed inExample 12 and of a NIST hydroxyapatite reference material weredetermined by placing the samples in a tris buffered saline solutions atpH 7.4 and measuring change in calcium concentration. FIG. 22 shows thedissolution results for the gallium-substituted SoDHA coating, and FIG.23 shows the dissolution results for the NIST standard. While the NISTsample stopped releasing calcium after less than two hours, thegallium-substituted SoDHA sample released calcium for more than 20 hourswith no clear dissolution plateau.

Example 17—Canine Study

The goal of this preclinical study was to determine the bone response toa gallium doped hydroxyapatite coating for orthopedic implants. Implantswere placed at either line-to-line fit or as gap-fit in trabecular sitesin dogs. Tissue was harvested 6 weeks after surgery. The outcomemeasures were implant fixation (measured via destructive mechanicaltesting), bone ongrowth and bone ingrowth (measured via backscatteredscanning electron microscopy and histology) and new bone fill within thegap (measured via histology). Secondary measures included descriptivehistology to report the tissue response around implants, andquantification of the % residual gallium-substituted HA coating.

Implants were placed in cylindrical defects created in the cancellousbone of large, skeletally mature, mixed-breed hounds. A canine wasselected as a model for testing as the bone structure of canines closelyresembles human bone. The sites of implantation selected for this studyprovide a large volume of cancellous bone. A total of 5 dogs wereenrolled in this study. Five purpose-bred research hounds (22-27 kg)were used in this study. Skeletal maturity was confirmed by X-rayevidence of closed growth plates. The dogs were acclimated for a periodof at least two weeks prior to surgery. Animals were single-housedthroughout the study period. All five dogs were deemed healthy uponarrival and. examination by the attending veterinarian prior to surgeryrevealed no obvious abnormalities.

The effects of these coatings on implant fixation were assessed in both1 mm gap and line-to-line or exact fits, as they represent a range ofimplant to host bone fit scenarios that are encountered in total jointreplacement procedures in humans. Four defects per animal were createdin cancellous bone to create side-by-side regions with line-to-line and1 mm radial gap fits between the porous coated surface of 6 mm diameterimplants and the host bone. These defects were created bilaterally inthe proximal humerus, distal femur, and proximal tibia. Two additionaldefects per animal were created in cancellous bone distal to the firstdefect in the humerus, bilaterally, in order to place a single implantwith a 1 mm radial gap fit. This was done due to the limitation on thenumber of anatomical sites suitable for implantation of side by sideimplants in this model.

The following test articles were used:

Gription™ implants with SoDHA HA coating (HA version of the SoDHAcoating)—10 mm length and 11 mm length, 6 mm (line-to-line implant) or 8mm diameter (1 mm gap implant).

Gription™ with gallium-substituted SoDHA HA coating (gallium-substitutedHA version of the SoDHA coating)—10 mm length and 11 mm length, 6 mm(line-to-line implant) or 8 mm diameter (1 mm gap implant).

All of the experimental work in this study w reviewed and approved bythe local institutional animal care and use committee (protocol#2008A0083-R2, approved Jun. 23, 2014). The animals in this study werehandled and maintained in accordance with the requirements of the AnimalWelfare Act.

Dogs were housed in cages with stainless steel runs, and approximately24 square feet of floor space. Floors were elevated with vinyl coatedexpanded mesh floors that were removable for sanitation. Cages werehosed clean at least once daily or more frequently as needed to preventaccumulation of excreta. Animals may have remained in place during dailycleaning with measures taken to assure that the animals remained dry.All cleaning or disinfecting agents used in the vivarium were designatedas USDA “Food Safe” and approved for use by the Attending Veterinarian.

Sanitation of cages and holding rooms was performed using a pressurewasher or other approved agent every 2-6 weeks (frequency based onbiological monitoring). Animals were removed from the cage duringsanitation to prevent exposure to hot water or disinfectant solutions.All surfaces of the cage and the room were rinsed thoroughly whendisinfectant solutions were used.

Dogs were fed an amount appropriate for their weight and activityaccording to USDA and National Research Council regulations. All feedwas provided in stainless steel bowls. All animals not scheduled for aprocedure were fed at least once daily. Animals scheduled for aprocedure were fasted 12-24 hours before the procedure. There were noknown contaminants considered to interfere with the validity of thestudy.

The animals on this study had free access to fresh clean water and noknown contaminants considered to interfere with the validity of thestudy.

Animals were administered a pre-operative tranquilizer of acepromazine(0.05 mg/kg IM) and general anesthesia induced with an intravenousinjection of ketamine hydrochloride and diazepam. Dogs were intubatedand anesthesia maintained with an inhaled mixture of isoflurane inoxygen. The surgical plane was assessed by monitoring pulse, heart rate,respiration and reflexes (ocular, pinch). An intravenous catheter wasplaced in the cephalic vein and perioperative antibiotic (cefazolin)administered. Sterile isotonic fluids (LRS or similar) was delivered atmaintenance doses through-out the surgical procedure. All four limbswere prepared for surgery in sequential fashion, with the hair beingclipped (elbow up to the proximal scapula for the forelimb; hock up tohip for the hind limb). After initial skin preparation with surgicalantiseptic, the dogs were transferred to the operating room and placedin lateral recumbency. The uppermost forelimb and hind limb weresuspended from an intravenous stand with tape, and the lateral aspectsof the humerus and femur were scrubbed with a combination of surgicalantiseptic (povidone-iodine or chlorhexidine) and alcohol. The surgicalsites were isolated with sterile drapes and an adhesive antimicrobialincise drape (Ioban 2; 3M, St. Paul, Minn.). Small incisions (<20 mm inlength) were made over the lateral aspect of the proximal humerus andthe distal aspect of the lateral femur, exposing the metaphyseal regionsof each bone. Guide wires were placed using a drill, and fluoroscopyused to confirm that the guide wires were oriented into the trabecularbone at 90 degrees to the cortical surface. A cannulated drill bit wasthen used to drill a hole that is 6 mm in diameter and 20 mm in overalllength. The proximal half of the drill hole was over-drilled to a finaldiameter of 8 mm. The same procedure was used in both the humerus andfemur. A total of four implants were placed—a 6 mm implant inserted intoeach defect and seated fully into the distal one-half of the drill holeusing a custom impactor. An 8-mm implant (consisting of a 6-mm corediameter implant with 8-mm washers at each end) was then placed into thedrill hole and seated fully. In this way, each bone defect contained oneimplant with a line-to-line fit at the implant-bone interface, and oneimplant with a circumferential 1-mm gap between the gallium-substitutedHA-coated implant and the surrounding bone. Following placement of thehumeral and femoral implants, the skin incision was closed withsubcuticular resorbable sutures (Monocryl, PDS II or similar) and therepair reinforced with skin staples. The wounds were covered withadhesive dressings, the dogs rolled onto the opposite site, the skinscrubbed, and the implants placed using exactly the same procedures asdescribed for the first side. After placement of the humeral and femoralimplants, the skin over the medial aspects of the left and right tibiawas scrubbed with a combination of surgical antiseptic (povidone-iodineor chlorhexidine) and alcohol. The surgical sites were isolated withsterile drapes and an adhesive antimicrobial incise drape (Ioban 2; 3M,St. Paul, Minn.). Small incisions (<20 mm in length) were made over themedial tibial metaphysis. A guide-wire was placed as before, and asingle drill hole (6 mm in diameter, 10 mm in length) made into thecancellous bone, at right angles to the medial tibial cortex. A 6 mmimplant, was placed in line-to-line fit, and the subcutis and skinclosed as described previously. Following surgery, the dogs weremonitored closed until recovered from anesthesia. The endotracheal tubewas removed when the dog regained its swallow reflex. Any IV catheterswere removed at this time. Post-operative pain management included anopiate analgesic (buprenorphine) every 6-12 hours for 3 dayspost-operatively. Non-steroidal anti-inflammatory agents (carprofen ormeloxicam) and antibiotics (cephalexin) were administered on the firstpost-operative morning and continued for 7-10 days post-surgery. Studyteam members monitored the dogs at least twice daily until skin stapleswere removed at 10-14 days post-surgery.

At the designated time point, dogs were euthanized with an intravenousoverdose of sodium pentobarbitone and death confirmed by an absence ofcardiorespiratory activity. The surgical sites in the left and rightproximal humerus, distal femur and proximal tibia were exposed,photographed and then resected with a necropsy saw, taking care topreserve the integrity of the implant and surrounding bone. Contactradiographs were made in two planes in order to document the boneresponse around each implant. The bone specimens were examined bymicro-CT (30-μm resolution) and then packaged on ice for overnightshipment to DePuy Synthes Joint Replacement, Warsaw, Ind. Upon receiptat the Warsaw site, the specimens were bisected at right angles to theimplant axis, one half was used for mechanical testing at DePuy Synthes,and the other half was placed in 70% alcohol and returned to The OhioState University for undecalcified histology.

Example 18—Histology Results

Undecalcified histology was carried out with fixed specimens of theimplant-bone interface processed by the Technovit 7200 and sectioned atright angles to the implant axis using a diamond band saw. A customalignment jig was used to ensure accurate implant alignment andsectioning. Two sections were prepared from each implant. These sectionswere ground to a final thickness of 100-150 μm, polished and thensurface stained with Goldner's trichrome. The nature and extent of bonecontact, fibrous tissue formation and periprosthetic inflammation weredescribed.

Embedded blocks containing the implant-bone interface were polished,coated with graphite and examined using backscattered SEM. Grayscaleimages were obtained across the entire perimeter of the implant, and thefractional percentage of bone apposition and bone ingrowth within theimplant surface was measured using semi-automated image analysis(Bioquant Osteo II). The linear extent (%) of residual HA coating on theimplant surface was measured.

Histomorphometric analysis was performed blind to treatment on eachslide. Low power digital images were captured of each section thatincluded the gap and an additional amount of tissue surrounding eachimplant. Static histomorphometric analysis was completed to determine %bone apposition to the implant surface, % bone within the porous coatingand % bone within the gap area. Ingrowth was measured as % total voids.Additional parameters evaluated include average coating thickness. Theresults, averaged over the various specimens are shown in Table 8 forSoDHA HA, and gallium-substituted SoDHA HA gap implants. The dataillustrating the benefit for bone ingrowth of adding Ga are alsopresented graphically in FIG. 25.

TABLE 8 Histomorphometry Results Gap implants % Ingrowth % AppositionSoDHA 11.6 ± 6.8  12.5 ± 3.6  SoDHA-Gallium 24.6 ± 11.2 22.6 ± 10.4

Histology data suggested that Gription™ SoDHA-gallium implants performedsignificantly (˜2×) better than both Gription™ SoDHA in the upperproximal humerus. Based on a lack of inflammation, particles andradiolucency surrounding the implants, there was no adverse response tothe implants or the test HA coatings detected at any of the implantsites 6 weeks after implantation.

Example 19—Organic Solvent Exchange and Supercritical CO₂ SolventExtraction

Coated Gription™ and grit blast-flat coupons were rinsed with DI waterafter forming the SoDHA-G coating as described in Example 12. Residualaqueous solvent was exchanged with ethanol 3 times within a soakingstep. Soak periods studied were 1 and 20 hours. After organic solventexchange in ethanol, coupons were the placed on a rack and inserted intoa 100 ml stainless steel vessel. The coupons were covered with ethanoland the top vessel end-cap was closed. The CO₂ flow direction was fromthe top of the vessel and out the bottom. The vessel was pressurized to100 bar with liquid CO₂ and the liquid ethanol was displaced with liquidCO₂ at room temperature at approximately 2 liters/minute of gaseous CO₂flow. The displacement time was approximately ½ hour. After all theethanol was displaced, the vessel was heated to 38° C. and dried for 4hours with supercritical CO₂ at a flow rate of 5 liters/min gas. Afterthe allotted drying time of 4 hours, the vessel was depressurized toatmosphere while maintaining the temperature above the CO₂ criticaltemperature of 32° C. The depressurization was conducted atapproximately 1 liter/minute gas flow rate and lasted approximately ½hour.

The surface morphologies of the treated and untreated films wereexamined by a scanning electron microscope, as shown FIGS. 26A and 26B,respectively. The scCO₂ treatment greatly reduced cracks in SoDHA-Gcoatings compared to regular drying.

Example 20—Re-Precipitation Via Hydrothermal Treatment of SoDHA-G

The SoDHA-G coated coupons prepared according to Example 12 were quicklytransferred from DI water to a glass bottle containing either 15 mL 40mM phosphate-Ga (Pi) syrup prepared according to Example 4 or 15 ml2.2262 mM phosphate-Ga (Pi) stock prepared according to Example 4. Theglass bottle was then sealed with a cap. The hydrothermal treatment ofSoDHA-G films was performed at either 70° C. or 90° C. for 2 hours.After hydrothermal treatment, the SoDHA-G coated coupons were rinsedwith DI water excessively for one minute and placed in a 60° C. oven todry for 1 hour.

The surface morphologies of the SoDHA-G and hydrothermally treatedSoDHA-G (SoDHA-G-HT) films were examined by a scanning electronmicroscope (FE-SEM, Quanta 600 F). A scanning electron microscopy imagefor SoDHA-G is shown in FIG. 27. Scanning electron microscopy images forSoDHA-G-HT hydrothermally treated at 70° C. for 2 hours for filmstreated with phosphate-Ga stock and phosphate-Ga syrup are shown inFIGS. 28A and 28B, respectively. Scanning electron microscopy images forSoDHA-G-HT hydrothermally treated at 90° C. for 1 hour for films treatedwith phosphate-Ga stock and phosphate-Ga syrup are shown in FIGS. 29Aand 29B, respectively. Scanning electron microscopy images forSoDHA-G-HT hydrothermally treated at 90° C. for 2 hours for filmstreated with phosphate-Ga stock and phosphate-Ga syrup are shown inFIGS. 30A and 30B, respectively. FIGS. 26-30B reveal the improvement tocracking as a function of optimizing temperature and time ofhydrothermal treatment. The phase composition of the SoDHA and SoDHA-HTfilms was identified by X-ray diffractometry (Philips Analytical), usingCu Kα radiation at 45 kV, 40 mA. The X-ray diffraction patterns ofSoDHA, SoDHA-G and SoDHA-G HT (hydrothermally treated in Pi-Ga stock at90° C. for 2 hours) were collected between 4°-60° (20) at 0.02° step and0.01°/s, as shown in FIG. 31. The XRD results indicated that the (002)peak of hydroxyapatite was not shifted after hydrothermal treatment,showing no appreciable Ga loss from the lattice.

Five (5) SoDHA-G coated Gription™ coupons prepared according to Example12 were quickly transferred from DI water to a glass bottle containing250 mL 2.2262 mM phosphate-Ga (Pi) stock prepared according to Example4. Ten (10) SoDHA-G coated Gription™ coupons prepared according toExample 12 were quickly transferred from DI water to a glass bottlecontaining 250 mL 40 mM phosphate-Ga (Pi) syrup prepared according toExample 4. The glass bottles were then sealed with a cap. Thehydrothermal treatment of SoDHA-G films was performed at 90° C. for 2hours. After hydrothermal treatment, the SoDHA-G coated Gription™coupons were rinsed excessively with DI water for one minute and placedin a 60° C. oven to dry for 1 hour.

Hydrothermally treated and regularly dried (no hydrothermal treatment)coatings were dissolved in 0.1 M hydrochloric acid and solutionsanalyzed for gallium with inductively coupled plasma (ICP) atomicemission spectroscopy. The gallium content of coatings withouthydrothermal treatment and treated with phosphate-Ga stock were 2.58 wt% and 2.71 wt %, respectively. However, unexpectedly, the galliumcontent of coatings hydrothermally treated in phosphate-Ga syrupincreased to 5.67 wt %. This revealed that hydrothermal treatment inconcentrated gallium containing solutions was an effective method toincrease the gallium content in hydroxyapatite coatings.

Example 21—Crack Quantification

The crack improvement benefit of post treatment according to Examples 19and 20 was quantified using image analysis by measuring the number ofcrack intersections on a predetermined horizontal grid. Images weretaken at 1000× on the FEI Quanta 600 F SEM, and then imported into theAxio Vision software (AxioVision SE64 Release 4.9.1.0, from Carl ZeissMicroscopy GmbH) and 25 horizontal grid lines 193.5 μm in length andvertically 6 μm apart were placed over most of the image. The interceptsof the cracks in the image and grid lines were then manually marked. Theintercepts were chosen manually by the operator to eliminate softwaredriven errors. The number of intersections in this given area was usedas a quantitative measure of the extent of surface cracking of SoDHA-Gcoatings. A representative image illustrating the method is shown inFIG. 32.

SoDHA-G coatings on grit blast coupons that underwent normal drying at60° C. with no post-processing step exhibited over 600 intercepts, whilehydrothermally treated SoDHA-G coatings revealed crack interceptsbetween 200 and 400. SoDHA-G with optimized hydrothermal treatmentparameters exhibited minimal cracking, with fewer than 200 intercepts.The number of crack intersections and intercept density forrepresentative regularly dried and post-processed coatings are shown inTable 9.

TABLE 9 Crack intercept count and density for various post-processedsamples Number of Intercept density Sample Intercepts (intercepts/mm²)Grit blast sample - Flat 4050 654 17467 SoDHA G100 60° C. oven dried -no post-processing step Grit blast sample - Flat 4054 348 9294 SoDHA-GPiGa Syrup 85° C. 1 hr - hydrothermally treated (HT) Grit blast sample -Flat 4053 230 6142 SoDHA-G PiGa Stock 90° C. 2 hr HT Acetabular cupsample - Cup 30 801 102 SoDHA-G100 PiGa Syrup 90° C. 2 hr HT Acetabularcup sample - Cup 108 2884 414 SoDHA-G100 PiGa Syrup 90° C. 2 hr HTGription sample - Disk 26 60 1603 SoDHA-G100 90° C. HT 2 hr PiGa Stock,Vacuum Treated

While the invention has been illustrated and described in detail in thedrawings and foregoing description, such an illustration and descriptionis to be considered as exemplary and not restrictive in character, itbeing understood that only the illustrative embodiments have been shownand described and that all changes and modifications that come withinthe spirit of the invention are desired to be protected.

There is a plurality of advantages of the present invention arising fromthe various features of the gallium-substituted HA coatings describedherein. It will be noted that alternative embodiments of each of thecoatings of the present invention may not include all of the featuresdescribed yet benefit from at least some of the advantages of suchfeatures. Those of ordinary skill in the art may readily devise theirown implementations of calcium phosphate coatings that incorporate oneor more of the features of the present invention and fall within thespirit and scope of the present invention as defined by the appendedclaims.

1. An orthopedic implant comprising a metal surface and a hydroxyapatitelayer disposed on at least part of the metal surface, the hydroxyapatitelayer comprising gallium ions therein, wherein the hydroxyapatite layeris crystalline.
 2. The orthopedic implant of claim 1, wherein thehydroxyapatite layer, when subjected to XRD, produces a (002) XRD peakthat is shifted by about 0.001° 2θ to about 0.5° 2θ compared to the(002) XRD peak of crystalline hydroxyapatite without gallium.
 3. Theorthopedic implant of claim 1, wherein the hydroxyapatite layer, whensubjected to XRD, produces a (002) XRD peak that corresponds to ad-spacing shift of about 0.001 Å to about 0.05 Å compared to the (002)XRD peak of crystalline hydroxyapatite without gallium.
 4. Theorthopedic implant of claim 1, wherein the hydroxyapatite layer has anaverage crystallite size of less than about 75 nm.
 5. The orthopedicimplant of claim 1, wherein the hydroxyapatite layer has an averagecrystallite size of less than about 75 nm in the [001] direction.
 6. Theorthopedic implant of claim 1, wherein the hydroxyapatite layer, whensubjected to XRD, produces a (002) XRD peak and a (112) XRD peak, andthe (002) XRD peak has an intensity 1.5 to 10 times greater than the(112) XRD peak.
 7. The orthopedic implant of claim 1, wherein thehydroxyapatite layer continuously dissolves for more than 24 hours invitro.
 8. The orthopedic implant of claim 1, wherein the hydroxyapatitelayer comprises about 0 wt % to about 5 wt % carbonate.
 9. Theorthopedic implant of claim 1, wherein the gallium ions comprise about0.01 wt % to about 10 wt % of the hydroxyapatite layer.
 10. Theorthopedic implant of claim 1, wherein the hydroxyapatite layer is incontact with the metal surface.
 11. The orthopedic implant of claim 10,wherein the metal surface comprises a titanate.
 12. The orthopedicimplant of claim 11, wherein the metal surface comprises sodiumtitanate.
 13. The orthopedic implant of claim 1, wherein the metalsurface is a titanium surface that has been treated with hydroxide. 14.The orthopedic implant of claim 1, wherein the hydroxyapatite layer hasa crystallinity of about 70 wt % to about 100 wt %.
 15. The orthopedicimplant of claim 1, wherein the hydroxyapatite layer has a phase purityof crystalline hydroxyapatite of greater than 90%.
 16. The orthopedicimplant of claim 1, wherein the hydroxyapatite layer has a surface areaof about 15 m²/g to about 200 m²/g.
 17. An osteoconductive compositioncomprising hydroxyapatite, the hydroxyapatite comprising gallium ionstherein, wherein the hydroxyapatite is crystalline and wherein thehydroxyapatite, when subjected to XRD, produces a (002) XRD peak that isshifted by about 0.001° 2θ to about 2° 2θ compared to the (002) XRD peakof crystalline hydroxyapatite without gallium.
 18. The osteoconductivecomposition of claim 17, wherein the hydroxyapatite has an averagecrystallite size of less than about 75 nm in the [001] direction.
 19. Amethod of forming a hydroxyapatite coating, the method comprisingcontacting a metal surface with a supersaturated solution comprisingcalcium ions, phosphate ions, and gallium ions wherein the pH of thesolution varies by less than 0.2 pH unit/hour during the contactingstep.
 20. The method of claim 19, further comprising mixing a firstsolution comprising gallium ions and phosphate ions and a secondsolution comprising calcium ions to form a supersaturated solution andcontacting a metal surface with the supersaturated solution.
 21. Themethod of claim 19, wherein the hydroxyapatite coating is formedpredominantly through heterogeneous nucleation such that thesupersaturated solution remains visibly free of turbidity during thecontacting step.
 22. The method of claim 19, wherein at least twodeposition sequences are employed.
 23. The method of claim 19, whereinthe hydroxyapatite coating forms at a rate per unit surface area fromabout 0.01 mg/hr·mm² to 0.03 about mg/hr·mm².
 24. The method of claim19, wherein the initial pH of the supersaturated solution is from about7.5 to about 7.9, and the initial temperature of the supersaturatedsolution is from about 38° C. to about 60° C.
 25. The method of claim19, wherein the metal surface is a metal oxide surface.
 26. The methodof claim 19, wherein the concentration of calcium in the supersaturatedsolution is from about 1.4 mM to about 1.8 mM.
 27. The method of claim19, wherein the concentration of phosphate in the supersaturatedsolution is from about 2 mM to about 2.3 mM.
 28. The method of claim 19,further comprising removing the metal surface from the supersaturatedsolution after from about 0.5 hour to about 12 hours.
 29. The method ofclaim 19, further comprising heating the coating in a phosphate solutionto mitigate surface cracking.
 30. The method of claim 19, furthercomprising heating the coating in a gallium containing solution to raisethe coating gallium content up to 15 wt %.
 31. The method of claim 19,further comprising contact the coating with a supercritical fluid tomitigate surface cracking.